{"gene":"ANP32A","run_date":"2026-06-13T19:06:35","timeline":{"discoveries":[{"year":1996,"finding":"ANP32A (PHAP-I/I1PP2A) was identified as a potent heat-stable inhibitor of protein phosphatase 2A (PP2A), with half-maximal inhibition at ~4 nM, and did not affect PP1, PP2B, or PP2C activities.","method":"In vitro phosphatase activity assay using purified recombinant human PHAP-I against PP2A, PP1, PP2B, PP2C","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro enzymatic assay with purified recombinant protein, selectivity confirmed across multiple phosphatases","pmids":["8679524"],"is_preprint":false},{"year":2002,"finding":"ANP32A (pp32) is a subunit of the INHAT (inhibitor of acetyltransferases) complex and inhibits histone acetyltransferase (HAT) activity of p300/CBP and PCAF by masking histones; its INHAT domains mediate histone binding, HAT inhibition, and transcriptional repression in vivo.","method":"In vitro HAT inhibition assays, colocalization and transfection studies, deletion/domain analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro HAT assay plus in vivo transfection and domain mapping, replicated in subsequent studies","pmids":["11830591"],"is_preprint":false},{"year":2004,"finding":"ANP32A (pp32/Set-TAF-Ibeta) specifically binds to unacetylated and hypoacetylated histones but not hyperacetylated histones, associates with histone deacetylases in vitro and in vivo, and associates with an endogenous estrogen receptor-regulated gene (EB1) in the hypoacetylated transcriptionally inactive state but not in the active state.","method":"Histone binding assays, co-immunoprecipitation with HDACs, chromatin immunoprecipitation at endogenous gene","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (binding assays, Co-IP, ChIP) with in vivo and in vitro validation","pmids":["15136563"],"is_preprint":false},{"year":2008,"finding":"ANP32A (PHAPI) promotes apoptosome formation by working together with CAS and Hsp70 to accelerate nucleotide exchange on Apaf-1 and prevent inactive Apaf-1/cytochrome c aggregation, thereby enhancing caspase-9 activation.","method":"Biochemical reconstitution of apoptosome activity, identification of CAS and Hsp70 as co-mediators, siRNA knockdown in cells measuring Apaf-1 aggregation and apoptosis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstitution assay plus RNAi cell-based validation with mechanistic definition of co-factors","pmids":["18439902"],"is_preprint":false},{"year":2008,"finding":"ANP32A (pp32/PHAP-I) promotes cytoplasmic translocation of HuR upon lethal stress; in the cytoplasm, ANP32A facilitates caspase-mediated cleavage of HuR at Asp226, amplifying the apoptotic response. siRNA depletion of ANP32A reduces both HuR cytoplasmic accumulation and caspase activation efficiency.","method":"siRNA knockdown, co-immunoprecipitation, HuR cleavage assays, non-cleavable mutant (D226A) overexpression","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional experiments (KD + mutagenesis + Co-IP) in multiple cell lines","pmids":["18180367"],"is_preprint":false},{"year":2008,"finding":"ANP32A (I1PP2A) interacts specifically with the catalytic subunit of PP2A (PP2Ac) but not with regulatory A or B subunits; the N-terminal isotype-specific region of ANP32A is required for PP2Ac association and PP2A inhibition. Overexpression of ANP32A in PC12/Tau441 cells increases Tau phosphorylation and impairs microtubule network and neurite outgrowth.","method":"GST pulldown, co-immunoprecipitation from transfected cells, deletion mutagenesis, in vitro phosphatase assay, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — GST pulldown + Co-IP + mutagenesis + functional tau phosphorylation readout","pmids":["18245083"],"is_preprint":false},{"year":2004,"finding":"ANP32A (pp32) directly binds to casein kinase II (CKII), which phosphorylates pp32 at serines 158 and 204 in vivo. Mutagenesis of these sites affects pp32 function.","method":"In vitro kinase assay, biochemical purification, deletion and site-directed mutagenesis, phospho-specific antibody validation","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with biochemical purification and site-specific mutagenesis, single lab","pmids":["15287743"],"is_preprint":false},{"year":2016,"finding":"Species-specific differences in ANP32A account for the suboptimal activity of avian influenza polymerase in mammalian cells. Avian ANP32A has an additional 33 amino acids between the LRR and LCAR domains; deletion of this insertion abrogates support of avian polymerase, and its insertion into human ANP32A rescues avian virus polymerase function. ANP32A is an essential host partner co-opted to support influenza virus replication.","method":"Rescue experiments with avian ANP32A in mammalian cells, deletion and insertion mutagenesis, influenza polymerase activity assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mutagenesis plus functional polymerase assays, published in high-impact journal, independently replicated","pmids":["26738596"],"is_preprint":false},{"year":2020,"finding":"Cryo-EM structures of influenza C virus polymerase in complex with human and chicken ANP32A reveal that two FluPol molecules form an asymmetric dimer bridged by the N-terminal LRR domain of ANP32A, while the C-terminal LCAR of ANP32A inserts between the two juxtaposed PB2 627 domains, providing a structural mechanism for how PB2(E627K) enables mammalian adaptation.","method":"Cryo-electron microscopy structure determination of FluPolC–ANP32A complexes","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structures of the complex with both human and chicken ANP32A","pmids":["33208942"],"is_preprint":false},{"year":2015,"finding":"ANP32A (pp32) and ANP32B (APRIL) constitute host-derived IREF-2 activity that interacts with free viral RNA-dependent RNA polymerase and preferentially upregulates vRNA synthesis from cRNA templates. Knockdown of these proteins reduces viral replication in vivo.","method":"Biochemical complementation assay with nuclear extracts, protein identification by mass spectrometry, siRNA knockdown","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical complementation assay plus MS identification and functional knockdown validation","pmids":["26512887"],"is_preprint":false},{"year":2020,"finding":"NMR analysis of PB2 627-NLS domains in complex with avian and human ANP32A shows that human ANP32A IDD transiently binds the 627 domain via multivalent interactions; PB2-E627 disrupts polyvalency of this interaction, an effect compensated by the avian-unique 33-aa motif in avian ANP32A IDD.","method":"NMR spectroscopy, conformational ensemble determination of PB2 627-NLS/ANP32A complexes","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure determination of complexes, single lab but rigorous structural method","pmids":["32694517"],"is_preprint":false},{"year":2004,"finding":"Tyrosine phosphorylation of ANP32A (PHAPI/pp32) by jacalin stimulation releases PP2A from ANP32A inhibition, thereby activating PP2A and leading to dephosphorylation of MEK1/2 and ERK1/2. PHAPI knockdown by RNAi abolished both PP2A activation and MEK inhibition by jacalin.","method":"Immunoprecipitation kinase assays, PP2A activity assay, siRNA knockdown, Western blot of MEK/ERK phosphorylation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, phosphatase activity assay, and RNAi functional validation, single lab","pmids":["15247276"],"is_preprint":false},{"year":2000,"finding":"ANP32A (I1PP2A) associates with the catalytic subunit of PP1 in the presence of Mn2+ and modifies its substrate specificity, stimulating PP1 activity toward myelin basic protein and histone H1 (but not phosphorylase) by 15–20 fold, an activity not seen with Co2+, Mg2+, Ca2+, or Zn2+.","method":"In vitro phosphatase activity assay, gel filtration co-elution with Mn2+, recombinant proteins","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro reconstitution with purified recombinant proteins and multiple substrate tests","pmids":["10734057"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of the N-terminal LRR domain of pp32 (ANP32A) was determined, revealing a capped leucine-rich repeat fold that mediates protein-protein interactions characteristic of the ANP32 family.","method":"X-ray crystallography","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure, single lab, validated by subsequent higher-resolution structures","pmids":["17567741"],"is_preprint":false},{"year":2005,"finding":"ANP32A (pp32/LANP) interacts with adenovirus E4orf6, which exports pp32 from the nucleus to the cytoplasm along with HuR; this complex stabilizes ARE-containing mRNAs (c-fos, c-myc, COX-2) in the cytoplasm via a CRM1-independent mechanism.","method":"Co-immunoprecipitation, subcellular fractionation, mRNA stability assays, CRM1 inhibitor (leptomycin B) experiments","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional mRNA assays in single lab","pmids":["15983058"],"is_preprint":false},{"year":2005,"finding":"Adenovirus protein VII associates with ANP32A (pp32) and SET in vitro, with distinct protein VII domains responsible for binding each; protein VII, ANP32A, and SET co-associate with viral DNA during early infection.","method":"In vitro binding assays, chromatin immunoprecipitation, immunofluorescence","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding and ChIP, single lab","pmids":["15681448"],"is_preprint":false},{"year":2007,"finding":"ANP32A (LANP) forms a complex with transcriptional repressor E4F and modulates its repressive activity; ataxin-1 competes with E4F for LANP binding, relieving LANP-E4F-mediated transcriptional repression. This links ANP32A to SCA1 pathology.","method":"Co-immunoprecipitation, transcriptional reporter assays, competition binding experiments","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus functional transcription assays, single lab","pmids":["17557114"],"is_preprint":false},{"year":2005,"finding":"ANP32A (pp32) tumor suppression requires amino acids 150–174; deletion or truncation of this region abolishes inhibition of oncogene-mediated (RAS+MYC) transformation in rat embryo fibroblasts. The oncogenic pp32r1 and pp32r2 differ from pp32 precisely in this region.","method":"Deletion and truncation mutagenesis, rat embryo fibroblast transformation assays (focus formation, soft agar)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional mutagenesis in cell transformation assay, single lab","pmids":["10400610"],"is_preprint":false},{"year":2005,"finding":"Hyperphosphorylated Rb interacts with ANP32A (pp32) but not with closely related pp32r1 or pp32r2; this Rb-pp32 interaction inhibits the apoptotic activity of pp32 and stimulates cell proliferation.","method":"Co-immunoprecipitation, apoptosis functional assays, proliferation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP with functional apoptosis and proliferation readouts, single lab","pmids":["15716273"],"is_preprint":false},{"year":2009,"finding":"ANP32A (PHAPI) apoptotic activity—stimulation of caspase activation via the apoptosome—is required for its tumor suppressive function. The PHAPI close homolog pp32R1 (an oncoprotein) cannot stimulate caspase activation; the critical difference maps to amino acids in the caspase activation motif. ANP32A translocates from nucleus to cytoplasm during apoptosis; disruption of its NLS modestly decreases tumor suppression.","method":"Truncation mutagenesis, in vitro caspase activation assay, subcellular fractionation, tumor suppression assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple truncation mutants with in vitro caspase assay and localization studies, single lab","pmids":["19121999"],"is_preprint":false},{"year":2010,"finding":"Sphingosine (and DMS, phytosphingosine) directly binds ANP32A identified by affinity chromatography/proteomics; sphingoid base binding relieves ANP32A-mediated PP2A inhibition in vitro and activates PP2A in endothelial cells, leading to p38 SAPK activation and COX-2 induction. ANP32A siRNA knockdown enhanced basal and DMS-activated PP2A activity.","method":"Affinity chromatography with sphingosine, proteomics, in vitro PP2A activity assay, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity chromatography plus in vitro PP2A assay and siRNA functional validation, single lab","pmids":["20558741"],"is_preprint":false},{"year":2009,"finding":"ANP32A (LANP) depletion promotes neurite outgrowth in neuronal cell lines and primary neurons from LANP null mice; LANP directly binds the neurofilament light chain (NF-L) gene promoter and suppresses histone acetylation at this locus, repressing NF-L expression.","method":"siRNA knockdown in neuronal cell lines, primary neuron culture from LANP KO mice, ChIP at NF-L promoter, histone acetylation analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse primary neurons + ChIP + functional phenotype, single lab","pmids":["19136565"],"is_preprint":false},{"year":2011,"finding":"ANP32A (pp32) interacts with STAT1 and STAT2 in an IFN-dependent manner and is required for maximal transcriptional induction of IFN-stimulated genes (ISGs) by promoting assembly of transcription initiation complexes at ISG promoters; siRNA knockdown of pp32 reduces histone acetylation on ISG promoters.","method":"Co-immunoprecipitation (IFN-dependent), ChIP at ISG promoters, siRNA knockdown with IFN-stimulated gene expression readout","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + ChIP + functional siRNA, single lab","pmids":["21325029"],"is_preprint":false},{"year":2017,"finding":"ANP32A (PP32) and SET/TAF-Iβ are components of the newly synthesized histone H4 complex identified by proteomics; they function to prevent HAT1-mediated acetylation of H4K5 and H4K12 in vitro. Depletion of PP32 and SET/TAF-Iβ causes hyperacetylation of H4 lysine residues, destabilizes H4-Hsp90 interaction, and results in S-phase arrest.","method":"Proteomic analysis of newly synthesized H4 complex, in vitro HAT inhibition assay, siRNA knockdown with histone acetylation and cell cycle analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics + in vitro HAT assay + siRNA functional readouts, single lab","pmids":["28977641"],"is_preprint":false},{"year":2010,"finding":"ANP32A (pp32) overexpression in pancreatic cancer cells reduces HuR association with mRNAs encoding dCK, VEGF, and HuR itself; silencing pp32 enhances HuR binding to these mRNA targets, affecting gemcitabine sensitivity through altered dCK protein levels.","method":"RNA immunoprecipitation (RIP), overexpression and siRNA knockdown, mRNA binding assays, gemcitabine sensitivity assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RIP assay plus functional drug sensitivity readout, single lab","pmids":["21152064"],"is_preprint":false},{"year":2018,"finding":"ANP32A deficiency in AML cells reduces genome-wide histone H3 acetylation, with significant H3 acetylation changes at lipid metabolism genes (APOC1, PCSK9, P2RX1, LPPR3); overexpression of APOC1 partially rescues the proliferation defect of ANP32A-deficient AML cells.","method":"Genome-wide ChIP-seq for H3 acetylation, gene expression analysis, APOC1 overexpression rescue experiment","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq plus functional rescue, single lab","pmids":["29467488"],"is_preprint":false},{"year":2018,"finding":"ANP32A protects cartilage against oxidative stress and OA by promoting expression of ATM (a key cellular oxidative defense regulator); Anp32a-deficient mice show reduced ATM expression and develop OA, osteopenia, and cerebellar ataxia, all rescued by antioxidant treatment.","method":"Microarray profiling in Anp32a KO mice, in vivo OA model, antioxidant treatment, immunohistochemistry","journal":"Science translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with transcriptome profiling and rescue experiment, single lab","pmids":["30209244"],"is_preprint":false},{"year":2019,"finding":"ANP32A and ANP32B mediate nuclear export of unspliced/partially spliced HIV-1 mRNA via interactions with Rev and CRM1; double (but not single) knockout of ANP32A and ANP32B accumulates unspliced viral mRNA in the nucleus and reduces Gag protein expression; reconstitution of either restores viral production.","method":"Double knockout, RNA nuclear/cytoplasmic fractionation, co-immunoprecipitation with Rev and CRM1, Gag expression assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — double KO + Co-IP + reconstitution, single lab","pmids":["31444273"],"is_preprint":false},{"year":2019,"finding":"Human ANP32A or ANP32B alone is indispensable for human influenza A virus RNA replication; two amino acids at positions 129–130 of chicken ANP32B are responsible for its inability to support viral replication and its weak interaction with the viral polymerase complex.","method":"siRNA/KO of ANP32A and ANP32B, polymerase activity reporter assays, co-immunoprecipitation, site-directed mutagenesis","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO + polymerase assay + mutagenesis + Co-IP, single lab","pmids":["30996088"],"is_preprint":false},{"year":2020,"finding":"Swine ANP32A uniquely (among mammalian ANP32 proteins) supports avian influenza polymerase activity; this is mapped to amino acids 106V and 156S in swANP32A. Mutation of these residues weakens interaction with chicken viral polymerase and reduces polymerase activity. ANP32A knockout in pig (PK15) cells dramatically reduces avian influenza polymerase activity.","method":"Polymerase activity reporter assays, site-directed mutagenesis, co-immunoprecipitation, ANP32A knockout in pig cells","journal":"PLoS pathogens / Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — mutagenesis + KO + Co-IP, replicated in two independent papers","pmids":["32084248","32269123"],"is_preprint":false},{"year":2017,"finding":"Downregulating ANP32A in hippocampal CA3 of tau transgenic mice rescues memory loss and synaptic deficits by reducing INHAT complex formation and unmasking histones for acetylation; ANP32A levels are upregulated by tau accumulation, β-amyloid, and H2O2 via C/EBPβ activation.","method":"Lentiviral shRNA stereotaxic injection, Morris water maze, electrophysiology, Golgi staining, ChIP, Western blot","journal":"Molecular neurodegeneration","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD with multiple functional readouts, single lab","pmids":["28472990"],"is_preprint":false},{"year":2022,"finding":"ANP32A represses Wnt signaling in articular cartilage via histone acetylation masking; ANP32A co-immunoprecipitates with components at Wnt target gene loci, and its loss triggers Wnt hyper-activation and cardiac hypertrophy. Combined antioxidant and Wnt inhibitor treatment ameliorates OA in Anp32a-deficient mice.","method":"Co-immunoprecipitation, ChIP-qPCR, luciferase assays, Anp32a KO mouse DMM OA model, Wnt inhibitor/antioxidant treatment","journal":"Osteoarthritis and cartilage","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + ChIP + KO mouse functional model, single lab","pmids":["35227892"],"is_preprint":false},{"year":2004,"finding":"ANP32A (pp32) specifically binds to histone H3 and blocks both its acetylation and phosphorylation; pp32 overexpression inhibits cell growth in Jurkat T cells and directly initiates caspase activity and promotes granzyme A-mediated caspase-independent cell death.","method":"Histone binding assays, histone acetylation/phosphorylation analysis, caspase activity assay, cell growth assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct histone binding and caspase activation assays, single lab","pmids":["16341127"],"is_preprint":false},{"year":2006,"finding":"ANP32A (LANP/I1PP2A) is pulled down by the cytoplasmic domain of integrin α3A and co-localizes with integrin α3β1; GST-ANP32A pulls down both integrin α3β1 and PP1 from cell lysates, and PP1 can dephosphorylate integrin α3β1 at T1046 in vitro, suggesting ANP32A bridges PP1 and integrin α3β1.","method":"Affinity chromatography, GST pulldown, co-localization by immunofluorescence, in vitro phosphatase assay","journal":"Journal of neuroscience research","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — pulldown and co-localization assays, functional bridge proposed but not fully established, single lab","pmids":["17016859"],"is_preprint":false},{"year":2008,"finding":"The NMR solution structure of the ANP32A LRR domain was determined; the LRR domain interacts with the AXH domain of ataxin-1 with millimolar (very weak) affinity, suggesting additional partners or post-translational modification is needed for stable binding. Two-hybrid screening identified Clip-170/Restin as a new LRR domain partner.","method":"NMR spectroscopy, yeast two-hybrid screening, in vitro binding assay","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 1–3 / Moderate — NMR structure plus two-hybrid, weak affinity binding measured, single lab","pmids":["18410380"],"is_preprint":false},{"year":2017,"finding":"Direct species-independent interactions exist between all ANP32A splice variants and the PB2 polymerase subunit; this interaction is enhanced in the presence of viral genomic RNA. However, only avian ANP32A (containing the 33-aa or 29-aa insertion) restored RNP complex assembly and enhanced RNA synthesis for a restricted polymerase.","method":"Split luciferase complementation assays, co-immunoprecipitation, influenza minigenome assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple interaction assays plus functional polymerase readout, single lab","pmids":["30184493"],"is_preprint":false},{"year":2020,"finding":"Human ANP32A interacts weakly with influenza polymerase; the 33-aa insertion of avian ANP32A and a hydrophobic SIM-like sequence unique to avian ANP32A both promote stronger polymerase interaction. SUMOylation of the host cell contributes to vPol activity including avian ANP32A function.","method":"Split luciferase complementation, co-immunoprecipitation, in situ split Venus interaction, mutagenesis, SUMO pathway manipulation","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple interaction assays + mutagenesis, single lab","pmids":["28903035"],"is_preprint":false},{"year":2021,"finding":"ANP32A is required for both vRNA and cRNA synthesis by the influenza A virus polymerase (not just vRNA from cRNA as previously proposed); ANP32A is needed for the actively replicating polymerase but not the encapsidating polymerase.","method":"Minigenome assays with ANP32A knockout/rescue, virus infection studies, viral promoter mutations","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — minigenome assays plus KO functional analysis with promoter mutations, single lab","pmids":["34935435"],"is_preprint":false},{"year":2013,"finding":"ANP32A (LANP/pp32) interacts with LIM-homeodomain transcription factor LHX3 via the LHX3 carboxyl terminus; LANP is associated with LHX3 target genes in pituitary cells (by ChIP), and experimental alteration of LANP levels affects LHX3-mediated pituitary gene regulation.","method":"Mass spectrometry, biochemical domain mapping, co-immunoprecipitation, ChIP, gain/loss-of-function transcription assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — MS identification + Co-IP + ChIP + functional assays, single lab","pmids":["23861948"],"is_preprint":false},{"year":2024,"finding":"Human ANP32A is SUMOylated at K68 and K153 by the E3 SUMO ligase PIAS2α and deSUMOylated by SENP1; SUMOylated ANP32A recruits influenza NS2 via a SIM-SUMO interaction, facilitating ANP32A-supported avian polymerase activity and vRNP-ANP32A interactions.","method":"SUMOylation assays, mutagenesis of SUMOylation sites, co-immunoprecipitation, vRNP assembly assays, PIAS2α/SENP1 manipulation","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SUMOylation site mutagenesis + Co-IP + functional vRNP assay, single lab","pmids":["39737943"],"is_preprint":false},{"year":2023,"finding":"NMR characterization of ternary complexes shows avian ANP32A simultaneously binds influenza FluPol and NP via distinct linear motifs in its longer disordered domain; the 33-aa deletion in human ANP32A blocks this simultaneous colocalization. PB2-E627K mutation enables FluPol and NP to bind the same extended linear motif on human ANP32A in a highly dynamic multivalent ternary complex.","method":"NMR spectroscopy of ternary FluPol/NP/ANP32A complexes, interaction mapping","journal":"Journal of the American Chemical Society","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural characterization of ternary complex with mechanistic interpretation, single lab","pmids":["37707433"],"is_preprint":false},{"year":2022,"finding":"AIMP1 interacts with ANP32A (identified by protein chip assay) and this interaction regulates histone H3 acetylation in multiple myeloma cells; disruption of AIMP1 expression reduces H3 acetylation enrichment at GAREM2 locus and decreases ERK1/2 phosphorylation.","method":"Protein chip assay, co-immunoprecipitation, ChIP-seq, siRNA knockdown","journal":"Cancer communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — protein chip and Co-IP, mechanistic link to H3 acetylation suggested but limited functional validation of direct ANP32A mechanism","pmids":["36042007"],"is_preprint":false},{"year":2004,"finding":"ANP32A (pp32) overexpression suppresses Raf-1 activation, downregulating ERK activation; the C-terminal half of pp32 is required for Raf-1 suppression. siRNA knockdown of pp32 enhances ERK and MEK activation.","method":"Overexpression and siRNA knockdown, Western blot of Raf-1/MEK/ERK phosphorylation, deletion mutagenesis","journal":"Cancer letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — KD/OE with phosphorylation readout, pathway placement not biochemically direct, single lab single method","pmids":["16039954"],"is_preprint":false},{"year":2015,"finding":"Cranial high-resolution X-ray crystal structure of the ANP32A LRR domain was determined at 1.56 Å, showing displacement in the turn connecting α1 to β1 compared to prior 2.4/2.69 Å structures.","method":"X-ray crystallography at 1.56 Å resolution","journal":"Acta crystallographica Section F","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — high-resolution crystal structure, single lab, structural refinement of known domain","pmids":["26057796"],"is_preprint":false},{"year":2021,"finding":"ANP32A binds HMGA1 mRNA via RNA immunoprecipitation and maintains HMGA1 mRNA stability, thereby promoting HMGA1 protein expression and subsequent STAT3 activation in hepatocellular carcinoma cells.","method":"RNA immunoprecipitation (RIP), siRNA knockdown and overexpression, Western blot, xenograft model","journal":"Carcinogenesis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single RIP assay with functional readout, single lab, no direct binding mechanism established","pmids":["33332531"],"is_preprint":false}],"current_model":"ANP32A is a multifunctional nuclear phosphoprotein that acts as: (1) a potent endogenous inhibitor of PP2A (interacting specifically with its catalytic subunit) and a modifier of PP1 substrate specificity; (2) a core subunit of the INHAT complex that masks histones to inhibit acetyltransferases (p300/CBP, PCAF, HAT1) and repress transcription, with phosphorylation at Ser158/204 by casein kinase II regulating this activity; (3) a pro-apoptotic factor that, via its C-terminal LCAR domain, promotes apoptosome assembly by accelerating Apaf-1 nucleotide exchange (together with CAS and Hsp70) and facilitates cytoplasmic translocation of HuR for caspase-mediated cleavage; (4) an essential host cofactor for influenza A virus RNA polymerase, bridging two FluPol molecules via its LRR domain to form an asymmetric replication platform (cryo-EM structure established), with species-specific differences (a 33-aa avian-unique insertion in the LCAR) dictating which viral polymerase variants can be supported; and (5) a regulator of mRNA stability and nuclear export through interactions with HuR, CRM1, and Rev."},"narrative":{"mechanistic_narrative":"ANP32A is a small, leucine-rich-repeat nuclear phosphoprotein that integrates phosphatase regulation, chromatin acetylation control, apoptotic signaling, and host support of viral RNA replication [PMID:8679524, PMID:11830591, PMID:18439902]. As a phosphatase regulator it is a potent and selective heat-stable inhibitor of PP2A, binding specifically the PP2A catalytic subunit through its N-terminal isotype-specific region [PMID:8679524, PMID:18245083], while in the presence of Mn2+ it associates with the PP1 catalytic subunit and redirects its substrate specificity [PMID:10734057]; relief of PP2A inhibition by tyrosine phosphorylation or by direct binding of sphingoid bases links ANP32A to downstream MEK/ERK and p38 signaling [PMID:15247276, PMID:20558741], and its PP2A inhibition modulates Tau phosphorylation [PMID:18245083]. In the nucleus ANP32A is a core subunit of the INHAT complex that binds unacetylated/hypoacetylated histones and masks them from acetyltransferases such as p300/CBP and PCAF, thereby repressing transcription [PMID:11830591, PMID:15136563]; this histone-masking activity is regulated by casein kinase II phosphorylation at Ser158/Ser204 [PMID:15287743], operates on newly synthesized histone H4 to block HAT1-mediated acetylation [PMID:28977641], and shapes acetylation-dependent programs governing neurofilament expression, interferon-stimulated genes, and lipid-metabolism loci [PMID:19136565, PMID:21325029, PMID:29467488]. Through its C-terminal region ANP32A is pro-apoptotic and tumor-suppressive, promoting apoptosome assembly together with CAS and Hsp70 by accelerating Apaf-1 nucleotide exchange to enhance caspase-9 activation [PMID:18439902], with the caspase-activating motif being required for both apoptotic and tumor-suppressor function [PMID:10400610, PMID:19121999]. ANP32A also controls mRNA fate, promoting cytoplasmic translocation and caspase cleavage of HuR during lethal stress and modulating HuR–mRNA association [PMID:18180367, PMID:21152064]. Finally, ANP32A (redundantly with ANP32B) is an essential host cofactor for influenza A virus polymerase: it interacts directly with the PB2 subunit, an interaction enhanced by viral RNA, and bridges two FluPol molecules into an asymmetric replication platform via its N-terminal LRR domain while its C-terminal disordered LCAR inserts between the juxtaposed PB2 627 domains [PMID:33208942, PMID:30184493, PMID:34935435]. Species-specific support of avian polymerase is dictated by an avian-unique 33-amino-acid insertion in the disordered domain that restores multivalent binding lost with PB2-E627, explaining mammalian adaptation [PMID:26738596, PMID:32694517, PMID:37707433]. Anp32a-deficient mice develop osteoarthritis, osteopenia and cerebellar ataxia linked to defective oxidative defense (reduced ATM) and Wnt de-repression, establishing physiological roles in tissue protection [PMID:30209244, PMID:35227892].","teleology":[{"year":1996,"claim":"Established ANP32A as a dedicated enzyme regulator by showing it is a selective, high-affinity inhibitor of PP2A, defining its first molecular activity.","evidence":"In vitro phosphatase assays with purified recombinant protein against PP2A, PP1, PP2B, PP2C","pmids":["8679524"],"confidence":"High","gaps":["Did not define the structural basis of PP2A selectivity","Cellular consequences of PP2A inhibition not addressed"]},{"year":2000,"claim":"Extended the phosphatase-regulatory repertoire by showing ANP32A modifies PP1 substrate specificity in a Mn2+-dependent manner, indicating it is not solely a PP2A inhibitor.","evidence":"In vitro phosphatase assays and gel filtration co-elution with recombinant proteins and multiple substrates","pmids":["10734057"],"confidence":"High","gaps":["Physiological relevance of Mn2+-dependence unclear","No in vivo PP1 substrate identified"]},{"year":2002,"claim":"Defined a chromatin function by identifying ANP32A as an INHAT subunit that masks histones to inhibit HATs, establishing transcriptional repression as a core role.","evidence":"In vitro HAT inhibition assays, transfection/colocalization, domain deletion mapping","pmids":["11830591"],"confidence":"High","gaps":["Genome-wide targets not defined at this stage","Regulation of INHAT activity unaddressed"]},{"year":2004,"claim":"Connected ANP32A histone masking to gene-specific repression and showed selectivity for hypoacetylated histones plus HDAC association, integrating it into the acetylation cycle.","evidence":"Histone binding assays, Co-IP with HDACs, ChIP at an estrogen-regulated gene; separate H3-binding/caspase study","pmids":["15136563","16341127"],"confidence":"High","gaps":["Mechanism linking histone state to recruitment unresolved","Direct vs indirect HDAC association not separated"]},{"year":2004,"claim":"Identified post-translational control of ANP32A by CKII phosphorylation at Ser158/Ser204, providing a regulatory switch over its functions.","evidence":"In vitro kinase assay, biochemical purification, site-directed mutagenesis, phospho-specific antibodies","pmids":["15287743"],"confidence":"High","gaps":["Which functions each phosphosite controls not fully mapped","Upstream signals activating CKII on ANP32A unknown"]},{"year":2008,"claim":"Established the pro-apoptotic mechanism by showing ANP32A accelerates Apaf-1 nucleotide exchange with CAS and Hsp70 to promote apoptosome assembly, and links ANP32A to HuR cytoplasmic translocation/cleavage.","evidence":"Apoptosome reconstitution, siRNA knockdown, HuR cleavage assays with non-cleavable mutant","pmids":["18439902","18180367"],"confidence":"High","gaps":["How nuclear ANP32A reaches the cytoplasmic apoptosome not fully defined","Trigger coupling apoptosis to HuR translocation incomplete"]},{"year":2008,"claim":"Mapped the PP2A interaction to the N-terminal isotype-specific region and tied PP2A inhibition to a cellular readout (Tau phosphorylation), sharpening mechanism and function.","evidence":"GST pulldown, Co-IP, deletion mutagenesis, in vitro phosphatase assay, immunofluorescence","pmids":["18245083"],"confidence":"High","gaps":["Structural detail of the PP2Ac contact not resolved","In vivo Tau relevance limited to overexpression model"]},{"year":2015,"claim":"Defined ANP32A (with ANP32B) as host IREF-2 activity that engages free influenza RdRp and promotes vRNA synthesis, opening the viral-cofactor branch.","evidence":"Biochemical complementation with nuclear extracts, MS identification, siRNA knockdown","pmids":["26512887"],"confidence":"High","gaps":["Direct polymerase contact not mapped here","Step-specificity of replication not fully resolved"]},{"year":2016,"claim":"Explained the avian-to-mammalian host barrier by showing an avian-unique 33-aa insertion governs which polymerases ANP32A can support, establishing it as an essential, species-restricting host factor.","evidence":"Rescue, deletion/insertion mutagenesis, polymerase activity assays in mammalian cells","pmids":["26738596"],"confidence":"High","gaps":["Atomic mechanism of the insertion's effect not yet defined","Whether PB2-627 directly contacts ANP32A unresolved at this stage"]},{"year":2019,"claim":"Demonstrated functional redundancy of ANP32A/ANP32B for human influenza replication and extended ANP32 to HIV-1 unspliced mRNA nuclear export via Rev/CRM1.","evidence":"Single/double knockouts, polymerase reporter assays, RNA fractionation, Co-IP with Rev and CRM1, reconstitution","pmids":["30996088","31444273"],"confidence":"Medium","gaps":["Direct vs scaffolding role in export not separated","Tissue-level relevance of redundancy untested"]},{"year":2020,"claim":"Provided structural mechanism: cryo-EM and NMR showed ANP32A bridges two FluPol via its LRR while the LCAR inserts between PB2 627 domains, explaining PB2-E627K mammalian adaptation through multivalent disordered-domain binding.","evidence":"Cryo-EM of FluPolC–ANP32A complexes; NMR of PB2 627-NLS/ANP32A complexes","pmids":["33208942","32694517"],"confidence":"High","gaps":["Dynamics of the asymmetric dimer in cells not directly observed","Generality across influenza A subtypes inferred from FluPolC"]},{"year":2020,"claim":"Refined the host-range determinants, showing swine ANP32A residues (106V/156S) uniquely permit avian polymerase support and that SUMO/SIM-like features modulate polymerase interaction strength.","evidence":"Polymerase reporter assays, mutagenesis, Co-IP, ANP32A knockout in pig cells; split-luciferase interaction assays","pmids":["32084248","32269123","28903035"],"confidence":"Medium","gaps":["Quantitative contribution of each feature to replication not partitioned","In vivo cross-species transmission impact not tested"]},{"year":2021,"claim":"Revised the replication-step model by showing ANP32A is required for both vRNA and cRNA synthesis and specifically for the actively replicating, not encapsidating, polymerase.","evidence":"Minigenome assays with knockout/rescue, infection studies, promoter mutations","pmids":["34935435"],"confidence":"Medium","gaps":["Molecular distinction between replicating and encapsidating polymerase engagement unresolved","Step-specific structural state not captured"]},{"year":2018,"claim":"Established physiological roles via knockout mice, linking ANP32A to oxidative defense (ATM) and acetylation-dependent gene programs in cartilage and leukemia.","evidence":"Anp32a KO mice, OA models, ChIP-seq for H3 acetylation, rescue experiments","pmids":["30209244","29467488"],"confidence":"Medium","gaps":["Direct vs indirect control of ATM/lipid genes not fully separated","Tissue specificity of acetylation targets incomplete"]},{"year":2023,"claim":"Resolved the multivalent ternary-complex logic, showing avian ANP32A simultaneously binds FluPol and NP through distinct linear motifs and that PB2-E627K rescues this on human ANP32A.","evidence":"NMR of FluPol/NP/ANP32A ternary complexes with interaction mapping","pmids":["37707433"],"confidence":"High","gaps":["Functional output of NP co-recruitment in replication not quantified in cells","Order of assembly events unresolved"]},{"year":2024,"claim":"Added a SUMO regulatory layer, showing PIAS2α-mediated SUMOylation at K68/K153 recruits influenza NS2 via SIM-SUMO contacts to facilitate avian polymerase support.","evidence":"SUMOylation assays, site mutagenesis, Co-IP, vRNP assembly assays, PIAS2α/SENP1 manipulation","pmids":["39737943"],"confidence":"Medium","gaps":["Whether SUMOylation also regulates non-viral ANP32A functions untested","Dynamics of SUMO cycling during infection unclear"]},{"year":null,"claim":"How ANP32A's multiple activities (phosphatase inhibition, histone masking, apoptosome promotion, viral polymerase support) are coordinated and switched within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking post-translational modifications to selection among competing functions","Structural basis of PP2A and PP1 contacts unsolved","Mechanism controlling nuclear-cytoplasmic redistribution across contexts undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5,12,11,20]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[1,2,23,32]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,21,22]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,8,35]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[9,24,35]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2,19]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,14,19]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,2,23]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,4,19]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,8,9,27]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4,24,27]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,11,20]}],"complexes":["INHAT complex","apoptosome (Apaf-1)","influenza FluPol replication platform","newly synthesized histone H4 complex"],"partners":["PP2A CATALYTIC SUBUNIT","PP1","HUR","APAF-1","CRM1","PB2 (INFLUENZA POLYMERASE)","CSNK2 (CASEIN KINASE II)","ANP32B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P39687","full_name":"Acidic leucine-rich nuclear phosphoprotein 32 family member A","aliases":["Acidic nuclear phosphoprotein pp32","pp32","Leucine-rich acidic nuclear protein","LANP","Mapmodulin","Potent heat-stable protein phosphatase 2A inhibitor I1PP2A","Putative HLA-DR-associated protein I","PHAPI"],"length_aa":249,"mass_kda":28.6,"function":"Multifunctional protein that is involved in the regulation of many processes including tumor suppression, apoptosis, cell cycle progression or transcription (PubMed:10400610, PubMed:11360199, PubMed:16341127, PubMed:18439902). Promotes apoptosis by favouring the activation of caspase-9/CASP9 and allowing apoptosome formation (PubMed:18439902). In addition, plays a role in the modulation of histone acetylation and transcription as part of the INHAT (inhibitor of histone acetyltransferases) complex. Inhibits the histone-acetyltranferase activity of EP300/CREBBP (CREB-binding protein) and EP300/CREBBP-associated factor by histone masking (PubMed:11830591). Preferentially binds to unmodified histone H3 and sterically inhibiting its acetylation and phosphorylation leading to cell growth inhibition (PubMed:16341127). Participates in other biochemical processes such as regulation of mRNA nuclear-to-cytoplasmic translocation and stability by its association with ELAVL1 (Hu-antigen R) (PubMed:18180367). Plays a role in E4F1-mediated transcriptional repression as well as inhibition of protein phosphatase 2A (PubMed:15642345, PubMed:17557114) (Microbial infection) Plays an essential role in influenza A, B and C viral genome replication (PubMed:30666459, PubMed:32694517, PubMed:33045004, PubMed:33208942). Mechanistically, mediates the assembly of the viral replicase asymmetric dimers composed of PB1, PB2 and PA via its N-terminal region (PubMed:33208942). Also plays an essential role in foamy virus mRNA export from the nucleus (PubMed:21159877)","subcellular_location":"Nucleus; Cytoplasm; Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/P39687/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANP32A","classification":"Not Classified","n_dependent_lines":16,"n_total_lines":1208,"dependency_fraction":0.013245033112582781},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"KPNA1","stoichiometry":10.0},{"gene":"ACTR2","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"ELOVL1","stoichiometry":0.2},{"gene":"KPNA6","stoichiometry":0.2},{"gene":"SAR1B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ANP32A","total_profiled":1310},"omim":[{"mim_id":"619823","title":"ACIDIC NUCLEAR PHOSPHOPROTEIN 32 FAMILY, MEMBER B; ANP32B","url":"https://www.omim.org/entry/619823"},{"mim_id":"614019","title":"LISSENCEPHALY 4 WITH MICROCEPHALY; LIS4","url":"https://www.omim.org/entry/614019"},{"mim_id":"609611","title":"ACIDIC LEUCINE-RICH NUCLEAR PHOSPHOPROTEIN 32 FAMILY, MEMBER E; ANP32E","url":"https://www.omim.org/entry/609611"},{"mim_id":"609449","title":"NUDE NEURODEVELOPMENT PROTEIN 1; NDE1","url":"https://www.omim.org/entry/609449"},{"mim_id":"600832","title":"ACIDIC NUCLEAR PHOSPHOPROTEIN 32 FAMILY, MEMBER A; ANP32A","url":"https://www.omim.org/entry/600832"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Centrosome","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ANP32A"},"hgnc":{"alias_symbol":["LANP","PP32","I1PP2A","PHAPI","MAPM","mapmodulin"],"prev_symbol":["C15orf1"]},"alphafold":{"accession":"P39687","domains":[{"cath_id":"3.80.10.10","chopping":"2-144","consensus_level":"high","plddt":96.5966,"start":2,"end":144}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P39687","model_url":"https://alphafold.ebi.ac.uk/files/AF-P39687-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P39687-F1-predicted_aligned_error_v6.png","plddt_mean":79.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANP32A","jax_strain_url":"https://www.jax.org/strain/search?query=ANP32A"},"sequence":{"accession":"P39687","fasta_url":"https://rest.uniprot.org/uniprotkb/P39687.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P39687/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P39687"}},"corpus_meta":[{"pmid":"26738596","id":"PMC_26738596","title":"Species difference in ANP32A underlies influenza A virus polymerase host restriction.","date":"2016","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26738596","citation_count":257,"is_preprint":false},{"pmid":"8679524","id":"PMC_8679524","title":"Molecular identification of I1PP2A, a novel potent heat-stable inhibitor protein of protein phosphatase 2A.","date":"1996","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8679524","citation_count":161,"is_preprint":false},{"pmid":"33208942","id":"PMC_33208942","title":"Host ANP32A mediates the assembly of the influenza virus replicase.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/33208942","citation_count":136,"is_preprint":false},{"pmid":"11830591","id":"PMC_11830591","title":"Regulation of histone acetylation and transcription by nuclear protein pp32, a subunit of the INHAT complex.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11830591","citation_count":123,"is_preprint":false},{"pmid":"21317927","id":"PMC_21317927","title":"MicroRNA-21 targets tumor suppressor genes ANP32A and SMARCA4.","date":"2011","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/21317927","citation_count":121,"is_preprint":false},{"pmid":"1655467","id":"PMC_1655467","title":"A functional complex is formed in human T lymphocytes between the protein tyrosine phosphatase CD45, the protein tyrosine kinase p56lck and pp32, a possible common substrate.","date":"1991","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1655467","citation_count":120,"is_preprint":false},{"pmid":"18180367","id":"PMC_18180367","title":"Caspase-mediated cleavage of HuR in the cytoplasm contributes to pp32/PHAP-I regulation of apoptosis.","date":"2008","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18180367","citation_count":111,"is_preprint":false},{"pmid":"8192856","id":"PMC_8192856","title":"Purification and characterization of two putative HLA class II associated proteins: PHAPI and PHAPII.","date":"1994","source":"Biological chemistry Hoppe-Seyler","url":"https://pubmed.ncbi.nlm.nih.gov/8192856","citation_count":91,"is_preprint":false},{"pmid":"15136563","id":"PMC_15136563","title":"A signaling role of histone-binding proteins and INHAT subunits pp32 and Set/TAF-Ibeta in integrating chromatin hypoacetylation and transcriptional repression.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15136563","citation_count":83,"is_preprint":false},{"pmid":"18439902","id":"PMC_18439902","title":"PHAPI, CAS, and Hsp70 promote apoptosome formation by preventing Apaf-1 aggregation and enhancing nucleotide exchange on Apaf-1.","date":"2008","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/18439902","citation_count":80,"is_preprint":false},{"pmid":"26512887","id":"PMC_26512887","title":"pp32 and APRIL are host cell-derived regulators of influenza virus RNA synthesis from cRNA.","date":"2015","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/26512887","citation_count":74,"is_preprint":false},{"pmid":"18245083","id":"PMC_18245083","title":"I1PP2A affects tau phosphorylation via association with the catalytic subunit of protein phosphatase 2A.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18245083","citation_count":72,"is_preprint":false},{"pmid":"8970164","id":"PMC_8970164","title":"Structure of pp32, an acidic nuclear protein which inhibits oncogene-induced formation of transformed foci.","date":"1996","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/8970164","citation_count":71,"is_preprint":false},{"pmid":"30996088","id":"PMC_30996088","title":"Fundamental Contribution and Host Range Determination of ANP32A and ANP32B in Influenza A Virus Polymerase Activity.","date":"2019","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/30996088","citation_count":70,"is_preprint":false},{"pmid":"11360199","id":"PMC_11360199","title":"Tumor suppression and potentiation by manipulation of pp32 expression.","date":"2001","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11360199","citation_count":62,"is_preprint":false},{"pmid":"15247276","id":"PMC_15247276","title":"Protein phosphatase 2A, a negative regulator of the ERK signaling pathway, is activated by tyrosine phosphorylation of putative HLA class II-associated protein I (PHAPI)/pp32 in response to the antiproliferative lectin, jacalin.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15247276","citation_count":60,"is_preprint":false},{"pmid":"30184493","id":"PMC_30184493","title":"Differential Splicing of ANP32A in Birds Alters Its Ability to Stimulate RNA Synthesis by Restricted Influenza Polymerase.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30184493","citation_count":58,"is_preprint":false},{"pmid":"2836618","id":"PMC_2836618","title":"Properties of avian sarcoma-leukosis virus pp32-related pol-endonucleases produced in Escherichia coli.","date":"1988","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/2836618","citation_count":57,"is_preprint":false},{"pmid":"1352500","id":"PMC_1352500","title":"Four CD45/P56lck-associated phosphorproteins (pp29-pp32) undergo alterations in human T cell activation.","date":"1992","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1352500","citation_count":57,"is_preprint":false},{"pmid":"6091334","id":"PMC_6091334","title":"Requirement of the avian retrovirus pp32 DNA binding protein domain for replication.","date":"1984","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/6091334","citation_count":56,"is_preprint":false},{"pmid":"15681448","id":"PMC_15681448","title":"Adenovirus protein VII functions throughout early phase and interacts with cellular proteins SET and pp32.","date":"2005","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/15681448","citation_count":55,"is_preprint":false},{"pmid":"28903035","id":"PMC_28903035","title":"Functional Insights into ANP32A-Dependent Influenza A Virus Polymerase Host Restriction.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28903035","citation_count":55,"is_preprint":false},{"pmid":"6292495","id":"PMC_6292495","title":"Avian retrovirus pp32 DNA-binding protein. I. Recognition of specific sequences on retrovirus DNA terminal repeats.","date":"1982","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/6292495","citation_count":52,"is_preprint":false},{"pmid":"9492852","id":"PMC_9492852","title":"Novel nuclear phosphoprotein pp32 is highly expressed in intermediate- and high-grade prostate cancer.","date":"1998","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/9492852","citation_count":46,"is_preprint":false},{"pmid":"32694517","id":"PMC_32694517","title":"Molecular basis of host-adaptation interactions between influenza virus polymerase PB2 subunit and ANP32A.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32694517","citation_count":46,"is_preprint":false},{"pmid":"10400610","id":"PMC_10400610","title":"Identification of sequences required for inhibition of oncogene-mediated transformation by pp32.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10400610","citation_count":46,"is_preprint":false},{"pmid":"15983058","id":"PMC_15983058","title":"Adenovirus E4orf6 targets pp32/LANP to control the fate of ARE-containing mRNAs by perturbing the CRM1-dependent mechanism.","date":"2005","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15983058","citation_count":43,"is_preprint":false},{"pmid":"21152064","id":"PMC_21152064","title":"pp32 (ANP32A) expression inhibits pancreatic cancer cell growth and induces gemcitabine resistance by disrupting HuR binding to mRNAs.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21152064","citation_count":42,"is_preprint":false},{"pmid":"10734057","id":"PMC_10734057","title":"Protein phosphatase 2A inhibitors, I(1)(PP2A) and I(2)(PP2A), associate with and modify the substrate specificity of protein phosphatase 1.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10734057","citation_count":42,"is_preprint":false},{"pmid":"17567741","id":"PMC_17567741","title":"The crystal structure of the tumor suppressor protein pp32 (Anp32a): structural insights into Anp32 family of proteins.","date":"2007","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/17567741","citation_count":41,"is_preprint":false},{"pmid":"32084248","id":"PMC_32084248","title":"A unique feature of swine ANP32A provides susceptibility to avian influenza virus infection in pigs.","date":"2020","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/32084248","citation_count":40,"is_preprint":false},{"pmid":"20558741","id":"PMC_20558741","title":"Sphingosine interaction with acidic leucine-rich nuclear phosphoprotein-32A (ANP32A) regulates PP2A activity and cyclooxygenase (COX)-2 expression in human endothelial cells.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20558741","citation_count":40,"is_preprint":false},{"pmid":"37074204","id":"PMC_37074204","title":"Mammalian ANP32A and ANP32B Proteins Drive Differential Polymerase Adaptations in Avian Influenza Virus.","date":"2023","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/37074204","citation_count":39,"is_preprint":false},{"pmid":"17557114","id":"PMC_17557114","title":"The role of LANP and ataxin 1 in E4F-mediated transcriptional repression.","date":"2007","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/17557114","citation_count":38,"is_preprint":false},{"pmid":"17962813","id":"PMC_17962813","title":"pp32/PHAPI determines the apoptosis response of non-small-cell lung cancer.","date":"2007","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/17962813","citation_count":37,"is_preprint":false},{"pmid":"28472990","id":"PMC_28472990","title":"Downregulating ANP32A rescues synapse and memory loss via chromatin remodeling in Alzheimer model.","date":"2017","source":"Molecular neurodegeneration","url":"https://pubmed.ncbi.nlm.nih.gov/28472990","citation_count":37,"is_preprint":false},{"pmid":"2995920","id":"PMC_2995920","title":"Site-specific nicking at the avian retrovirus LTR circle junction by the viral pp32 DNA endonuclease.","date":"1985","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/2995920","citation_count":36,"is_preprint":false},{"pmid":"15060138","id":"PMC_15060138","title":"Generation and characterization of LANP/pp32 null mice.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15060138","citation_count":35,"is_preprint":false},{"pmid":"29467488","id":"PMC_29467488","title":"ANP32A regulates histone H3 acetylation and promotes leukemogenesis.","date":"2018","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/29467488","citation_count":35,"is_preprint":false},{"pmid":"15716273","id":"PMC_15716273","title":"Phosphorylated retinoblastoma protein complexes with pp32 and inhibits pp32-mediated apoptosis.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15716273","citation_count":35,"is_preprint":false},{"pmid":"32269123","id":"PMC_32269123","title":"Swine ANP32A Supports Avian Influenza Virus Polymerase.","date":"2020","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/32269123","citation_count":33,"is_preprint":false},{"pmid":"3009900","id":"PMC_3009900","title":"Nuclease mechanism of the avian retrovirus pp32 endonuclease.","date":"1986","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/3009900","citation_count":33,"is_preprint":false},{"pmid":"6320867","id":"PMC_6320867","title":"Avian retrovirus pp32 DNA binding protein. Preferential binding to the promoter region of long terminal repeat DNA.","date":"1984","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/6320867","citation_count":32,"is_preprint":false},{"pmid":"30209244","id":"PMC_30209244","title":"ANP32A regulates ATM expression and prevents oxidative stress in cartilage, brain, and bone.","date":"2018","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30209244","citation_count":32,"is_preprint":false},{"pmid":"15865439","id":"PMC_15865439","title":"Novel cytosolic binding partners of the neural cell adhesion molecule: mapping the binding domains of PLC gamma, LANP, TOAD-64, syndapin, PP1, and PP2A.","date":"2005","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15865439","citation_count":32,"is_preprint":false},{"pmid":"19136565","id":"PMC_19136565","title":"Neuronal differentiation is regulated by leucine-rich acidic nuclear protein (LANP), a member of the inhibitor of histone acetyltransferase complex.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19136565","citation_count":30,"is_preprint":false},{"pmid":"19121999","id":"PMC_19121999","title":"PHAPI/pp32 suppresses tumorigenesis by stimulating apoptosis.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19121999","citation_count":29,"is_preprint":false},{"pmid":"11678310","id":"PMC_11678310","title":"Expression of pp32 gene family members in breast cancer.","date":"2001","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/11678310","citation_count":28,"is_preprint":false},{"pmid":"31694956","id":"PMC_31694956","title":"Elucidating the Interactions between Influenza Virus Polymerase and Host Factor ANP32A.","date":"2020","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/31694956","citation_count":28,"is_preprint":false},{"pmid":"34935435","id":"PMC_34935435","title":"The Host Factor ANP32A Is Required for Influenza A Virus vRNA and cRNA Synthesis.","date":"2021","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/34935435","citation_count":28,"is_preprint":false},{"pmid":"21325029","id":"PMC_21325029","title":"pp32, an INHAT component, is a transcription machinery recruiter for maximal induction of IFN-stimulated genes.","date":"2011","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/21325029","citation_count":27,"is_preprint":false},{"pmid":"28977641","id":"PMC_28977641","title":"PP32 and SET/TAF-Iβ proteins regulate the acetylation of newly synthesized histone H4.","date":"2017","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/28977641","citation_count":26,"is_preprint":false},{"pmid":"28731192","id":"PMC_28731192","title":"ANP32A modulates cell growth by regulating p38 and Akt activity in colorectal cancer.","date":"2017","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/28731192","citation_count":23,"is_preprint":false},{"pmid":"14695340","id":"PMC_14695340","title":"pp32 reduction induces differentiation of TSU-Pr1 cells.","date":"2004","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/14695340","citation_count":23,"is_preprint":false},{"pmid":"24659532","id":"PMC_24659532","title":"Capping motifs stabilize the leucine-rich repeat protein PP32 and rigidify adjacent repeats.","date":"2014","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/24659532","citation_count":20,"is_preprint":false},{"pmid":"25589718","id":"PMC_25589718","title":"Inhibition of Protein Phosphatase-2A (PP2A) by I1PP2A Leads to Hyperphosphorylation of Tau, Neurodegeneration, and Cognitive Impairment in Rats.","date":"2015","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/25589718","citation_count":20,"is_preprint":false},{"pmid":"22884877","id":"PMC_22884877","title":"LANP mediates neuritic pathology in Spinocerebellar ataxia type 1.","date":"2012","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/22884877","citation_count":20,"is_preprint":false},{"pmid":"6314648","id":"PMC_6314648","title":"Antibodies against a synthetic peptide of the avian retrovirus pp32 protein and the beta DNA polymerase subunit.","date":"1983","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/6314648","citation_count":20,"is_preprint":false},{"pmid":"19565487","id":"PMC_19565487","title":"Variation at the ANP32A gene is associated with risk of hip osteoarthritis in women.","date":"2009","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/19565487","citation_count":19,"is_preprint":false},{"pmid":"6257933","id":"PMC_6257933","title":"Partial phosphorylation in vivo of the avian retrovirus pp32 DNA endonuclease.","date":"1980","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/6257933","citation_count":19,"is_preprint":false},{"pmid":"16039954","id":"PMC_16039954","title":"pp32/ I-1(PP2A) negatively regulates the Raf-1/MEK/ERK pathway.","date":"2004","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/16039954","citation_count":19,"is_preprint":false},{"pmid":"17906614","id":"PMC_17906614","title":"Reduction of pp32 expression in poorly differentiated pancreatic ductal adenocarcinomas and intraductal papillary mucinous neoplasms with moderate dysplasia.","date":"2007","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/17906614","citation_count":18,"is_preprint":false},{"pmid":"25902505","id":"PMC_25902505","title":"Highly polarized C-terminal transition state of the leucine-rich repeat domain of PP32 is governed by local stability.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25902505","citation_count":18,"is_preprint":false},{"pmid":"31444273","id":"PMC_31444273","title":"ANP32A and ANP32B are key factors in the Rev-dependent CRM1 pathway for nuclear export of HIV-1 unspliced mRNA.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31444273","citation_count":16,"is_preprint":false},{"pmid":"36042007","id":"PMC_36042007","title":"AIMP1 promotes multiple myeloma malignancy through interacting with ANP32A to mediate histone H3 acetylation.","date":"2022","source":"Cancer communications (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/36042007","citation_count":16,"is_preprint":false},{"pmid":"31608791","id":"PMC_31608791","title":"Insights into species-specific regulation of ANP32A on the mammalian-restricted influenza virus polymerase activity.","date":"2019","source":"Emerging microbes & infections","url":"https://pubmed.ncbi.nlm.nih.gov/31608791","citation_count":15,"is_preprint":false},{"pmid":"16341127","id":"PMC_16341127","title":"Tumor suppressor pp32 represses cell growth through inhibition of transcription by blocking acetylation and phosphorylation of histone H3 and initiating its proapoptotic activity.","date":"2005","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/16341127","citation_count":15,"is_preprint":false},{"pmid":"31037830","id":"PMC_31037830","title":"Bergapten alleviates osteoarthritis by regulating the ANP32A/ATM signaling pathway.","date":"2019","source":"FEBS open bio","url":"https://pubmed.ncbi.nlm.nih.gov/31037830","citation_count":15,"is_preprint":false},{"pmid":"2835511","id":"PMC_2835511","title":"Avian retrovirus pp32 DNA endonuclease is phosphorylated on Ser in the carboxyl-terminal region.","date":"1988","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/2835511","citation_count":14,"is_preprint":false},{"pmid":"35659510","id":"PMC_35659510","title":"Sevoflurane inhibits histone acetylation and contributes to cognitive dysfunction by enhancing the expression of ANP32A in aging mice.","date":"2022","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/35659510","citation_count":14,"is_preprint":false},{"pmid":"33332531","id":"PMC_33332531","title":"ANP32A promotes the proliferation, migration and invasion of hepatocellular carcinoma by modulating the HMGA1/STAT3 pathway.","date":"2021","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/33332531","citation_count":13,"is_preprint":false},{"pmid":"25866766","id":"PMC_25866766","title":"The expression and distributions of ANP32A in the developing brain.","date":"2015","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/25866766","citation_count":12,"is_preprint":false},{"pmid":"35227892","id":"PMC_35227892","title":"ANP32A represses Wnt signaling across tissues thereby protecting against osteoarthritis and heart disease.","date":"2022","source":"Osteoarthritis and cartilage","url":"https://pubmed.ncbi.nlm.nih.gov/35227892","citation_count":12,"is_preprint":false},{"pmid":"16009334","id":"PMC_16009334","title":"A pp32-retinoblastoma protein complex modulates androgen receptor-mediated transcription and associates with components of the splicing machinery.","date":"2005","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/16009334","citation_count":12,"is_preprint":false},{"pmid":"38295177","id":"PMC_38295177","title":"Avian ANP32A incorporated in avian influenza A virions promotes interspecies transmission by priming early viral replication in mammals.","date":"2024","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/38295177","citation_count":12,"is_preprint":false},{"pmid":"29782322","id":"PMC_29782322","title":"Inhibition of Histone Acetylation by ANP32A Induces Memory Deficits.","date":"2018","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/29782322","citation_count":11,"is_preprint":false},{"pmid":"20617464","id":"PMC_20617464","title":"CXCL12-mediated regulation of ANP32A/Lanp, a component of the inhibitor of histone acetyl transferase (INHAT) complex, in cortical neurons.","date":"2010","source":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20617464","citation_count":11,"is_preprint":false},{"pmid":"18410380","id":"PMC_18410380","title":"Structural bases for recognition of Anp32/LANP proteins.","date":"2008","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/18410380","citation_count":10,"is_preprint":false},{"pmid":"33982347","id":"PMC_33982347","title":"Asp149 and Asp152 in chicken and human ANP32A play an essential role in the interaction with influenza viral polymerase.","date":"2021","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/33982347","citation_count":9,"is_preprint":false},{"pmid":"28473768","id":"PMC_28473768","title":"Knockdown of pp32 Increases Histone Acetylation and Ameliorates Cognitive Deficits.","date":"2017","source":"Frontiers in aging neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/28473768","citation_count":9,"is_preprint":false},{"pmid":"36370958","id":"PMC_36370958","title":"Hypoxia and Wnt signaling inversely regulate expression of chondroprotective molecule ANP32A in articular cartilage.","date":"2022","source":"Osteoarthritis and cartilage","url":"https://pubmed.ncbi.nlm.nih.gov/36370958","citation_count":8,"is_preprint":false},{"pmid":"15287743","id":"PMC_15287743","title":"The identification of phosphorylation sites of pp32 and biochemical purification of a cellular pp32-kinase.","date":"2004","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15287743","citation_count":8,"is_preprint":false},{"pmid":"23861948","id":"PMC_23861948","title":"LHX3 interacts with inhibitor of histone acetyltransferase complex subunits LANP and TAF-1β to modulate pituitary gene regulation.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23861948","citation_count":8,"is_preprint":false},{"pmid":"37707433","id":"PMC_37707433","title":"Multivalent Dynamic Colocalization of Avian Influenza Polymerase and Nucleoprotein by Intrinsically Disordered ANP32A Reveals the Molecular Basis of Human Adaptation.","date":"2023","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/37707433","citation_count":8,"is_preprint":false},{"pmid":"29545082","id":"PMC_29545082","title":"High-Pressure NMR and SAXS Reveals How Capping Modulates Folding Cooperativity of the pp32 Leucine-rich Repeat Protein.","date":"2018","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/29545082","citation_count":8,"is_preprint":false},{"pmid":"32574681","id":"PMC_32574681","title":"SRSF10 inhibits the polymerase activity and replication of avian influenza virus by regulating the alternative splicing of chicken ANP32A.","date":"2020","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/32574681","citation_count":8,"is_preprint":false},{"pmid":"9146727","id":"PMC_9146727","title":"pp32 overexpression induces nuclear pleomorphism in rat prostatic carcinoma cells.","date":"1996","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/9146727","citation_count":8,"is_preprint":false},{"pmid":"30666459","id":"PMC_30666459","title":"The interaction of cellular protein ANP32A with influenza A virus polymerase component PB2 promotes vRNA synthesis.","date":"2019","source":"Archives of virology","url":"https://pubmed.ncbi.nlm.nih.gov/30666459","citation_count":7,"is_preprint":false},{"pmid":"17016859","id":"PMC_17016859","title":"Integrin alpha3beta1 interacts with I1PP2A/lanp and phosphatase PP1.","date":"2006","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/17016859","citation_count":6,"is_preprint":false},{"pmid":"36555564","id":"PMC_36555564","title":"Anp32a Promotes Neuronal Regeneration after Spinal Cord Injury of Zebrafish Embryos.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36555564","citation_count":6,"is_preprint":false},{"pmid":"34678588","id":"PMC_34678588","title":"Small peptide targeting ANP32A as a novel strategy for acute myeloid leukemia therapy.","date":"2021","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34678588","citation_count":6,"is_preprint":false},{"pmid":"35044222","id":"PMC_35044222","title":"KPNA6 is a Cofactor of ANP32A/B in Supporting Influenza Virus Polymerase Activity.","date":"2022","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/35044222","citation_count":5,"is_preprint":false},{"pmid":"38351418","id":"PMC_38351418","title":"H3K4 Trimethylation Mediate Hyperhomocysteinemia Induced Neurodegeneration via Suppressing Histone Acetylation by ANP32A.","date":"2024","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/38351418","citation_count":5,"is_preprint":false},{"pmid":"29106904","id":"PMC_29106904","title":"Prothymosin α interacts with SET, ANP32A and ANP32B and other cytoplasmic and mitochondrial proteins in proliferating cells.","date":"2017","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/29106904","citation_count":5,"is_preprint":false},{"pmid":"26867171","id":"PMC_26867171","title":"The Avian Influenza Virus Polymerase Brings ANP32A Home to Roost.","date":"2016","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/26867171","citation_count":5,"is_preprint":false},{"pmid":"39737943","id":"PMC_39737943","title":"Human ANP32A/B are SUMOylated and utilized by avian influenza virus NS2 protein to overcome species-specific restriction.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39737943","citation_count":4,"is_preprint":false},{"pmid":"17142970","id":"PMC_17142970","title":"Highly acidic C-terminal domain of pp32 is required for the interaction with histone chaperone, TAF-Ibeta.","date":"2006","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/17142970","citation_count":4,"is_preprint":false},{"pmid":"38421166","id":"PMC_38421166","title":"PB2 residue 473 contributes to the mammalian virulence of H7N9 avian influenza virus by modulating viral polymerase activity via ANP32A.","date":"2024","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/38421166","citation_count":4,"is_preprint":false},{"pmid":"26057796","id":"PMC_26057796","title":"High-resolution crystal structure of the leucine-rich repeat domain of the human tumour suppressor PP32A (ANP32A).","date":"2015","source":"Acta crystallographica. Section F, Structural biology communications","url":"https://pubmed.ncbi.nlm.nih.gov/26057796","citation_count":4,"is_preprint":false},{"pmid":"33686586","id":"PMC_33686586","title":"Gga-miR-181a modulates ANP32A expression and inhibits MDCC-MSB-1 cell.","date":"2021","source":"In vitro cellular & developmental biology. Animal","url":"https://pubmed.ncbi.nlm.nih.gov/33686586","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47397,"output_tokens":10186,"usd":0.14749,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20532,"output_tokens":5408,"usd":0.11893,"stage2_stop_reason":"end_turn"},"total_usd":0.26642,"stage1_batch_id":"msgbatch_0147LFpL5iCPFZF66xp23BqC","stage2_batch_id":"msgbatch_01Crtwc6eCsZh1CrnfJhY7J7","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"ANP32A (PHAP-I/I1PP2A) was identified as a potent heat-stable inhibitor of protein phosphatase 2A (PP2A), with half-maximal inhibition at ~4 nM, and did not affect PP1, PP2B, or PP2C activities.\",\n      \"method\": \"In vitro phosphatase activity assay using purified recombinant human PHAP-I against PP2A, PP1, PP2B, PP2C\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro enzymatic assay with purified recombinant protein, selectivity confirmed across multiple phosphatases\",\n      \"pmids\": [\"8679524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"ANP32A (pp32) is a subunit of the INHAT (inhibitor of acetyltransferases) complex and inhibits histone acetyltransferase (HAT) activity of p300/CBP and PCAF by masking histones; its INHAT domains mediate histone binding, HAT inhibition, and transcriptional repression in vivo.\",\n      \"method\": \"In vitro HAT inhibition assays, colocalization and transfection studies, deletion/domain analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro HAT assay plus in vivo transfection and domain mapping, replicated in subsequent studies\",\n      \"pmids\": [\"11830591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ANP32A (pp32/Set-TAF-Ibeta) specifically binds to unacetylated and hypoacetylated histones but not hyperacetylated histones, associates with histone deacetylases in vitro and in vivo, and associates with an endogenous estrogen receptor-regulated gene (EB1) in the hypoacetylated transcriptionally inactive state but not in the active state.\",\n      \"method\": \"Histone binding assays, co-immunoprecipitation with HDACs, chromatin immunoprecipitation at endogenous gene\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (binding assays, Co-IP, ChIP) with in vivo and in vitro validation\",\n      \"pmids\": [\"15136563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ANP32A (PHAPI) promotes apoptosome formation by working together with CAS and Hsp70 to accelerate nucleotide exchange on Apaf-1 and prevent inactive Apaf-1/cytochrome c aggregation, thereby enhancing caspase-9 activation.\",\n      \"method\": \"Biochemical reconstitution of apoptosome activity, identification of CAS and Hsp70 as co-mediators, siRNA knockdown in cells measuring Apaf-1 aggregation and apoptosis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstitution assay plus RNAi cell-based validation with mechanistic definition of co-factors\",\n      \"pmids\": [\"18439902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ANP32A (pp32/PHAP-I) promotes cytoplasmic translocation of HuR upon lethal stress; in the cytoplasm, ANP32A facilitates caspase-mediated cleavage of HuR at Asp226, amplifying the apoptotic response. siRNA depletion of ANP32A reduces both HuR cytoplasmic accumulation and caspase activation efficiency.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, HuR cleavage assays, non-cleavable mutant (D226A) overexpression\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional experiments (KD + mutagenesis + Co-IP) in multiple cell lines\",\n      \"pmids\": [\"18180367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ANP32A (I1PP2A) interacts specifically with the catalytic subunit of PP2A (PP2Ac) but not with regulatory A or B subunits; the N-terminal isotype-specific region of ANP32A is required for PP2Ac association and PP2A inhibition. Overexpression of ANP32A in PC12/Tau441 cells increases Tau phosphorylation and impairs microtubule network and neurite outgrowth.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation from transfected cells, deletion mutagenesis, in vitro phosphatase assay, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — GST pulldown + Co-IP + mutagenesis + functional tau phosphorylation readout\",\n      \"pmids\": [\"18245083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ANP32A (pp32) directly binds to casein kinase II (CKII), which phosphorylates pp32 at serines 158 and 204 in vivo. Mutagenesis of these sites affects pp32 function.\",\n      \"method\": \"In vitro kinase assay, biochemical purification, deletion and site-directed mutagenesis, phospho-specific antibody validation\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with biochemical purification and site-specific mutagenesis, single lab\",\n      \"pmids\": [\"15287743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Species-specific differences in ANP32A account for the suboptimal activity of avian influenza polymerase in mammalian cells. Avian ANP32A has an additional 33 amino acids between the LRR and LCAR domains; deletion of this insertion abrogates support of avian polymerase, and its insertion into human ANP32A rescues avian virus polymerase function. ANP32A is an essential host partner co-opted to support influenza virus replication.\",\n      \"method\": \"Rescue experiments with avian ANP32A in mammalian cells, deletion and insertion mutagenesis, influenza polymerase activity assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mutagenesis plus functional polymerase assays, published in high-impact journal, independently replicated\",\n      \"pmids\": [\"26738596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-EM structures of influenza C virus polymerase in complex with human and chicken ANP32A reveal that two FluPol molecules form an asymmetric dimer bridged by the N-terminal LRR domain of ANP32A, while the C-terminal LCAR of ANP32A inserts between the two juxtaposed PB2 627 domains, providing a structural mechanism for how PB2(E627K) enables mammalian adaptation.\",\n      \"method\": \"Cryo-electron microscopy structure determination of FluPolC–ANP32A complexes\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structures of the complex with both human and chicken ANP32A\",\n      \"pmids\": [\"33208942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ANP32A (pp32) and ANP32B (APRIL) constitute host-derived IREF-2 activity that interacts with free viral RNA-dependent RNA polymerase and preferentially upregulates vRNA synthesis from cRNA templates. Knockdown of these proteins reduces viral replication in vivo.\",\n      \"method\": \"Biochemical complementation assay with nuclear extracts, protein identification by mass spectrometry, siRNA knockdown\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical complementation assay plus MS identification and functional knockdown validation\",\n      \"pmids\": [\"26512887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NMR analysis of PB2 627-NLS domains in complex with avian and human ANP32A shows that human ANP32A IDD transiently binds the 627 domain via multivalent interactions; PB2-E627 disrupts polyvalency of this interaction, an effect compensated by the avian-unique 33-aa motif in avian ANP32A IDD.\",\n      \"method\": \"NMR spectroscopy, conformational ensemble determination of PB2 627-NLS/ANP32A complexes\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure determination of complexes, single lab but rigorous structural method\",\n      \"pmids\": [\"32694517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Tyrosine phosphorylation of ANP32A (PHAPI/pp32) by jacalin stimulation releases PP2A from ANP32A inhibition, thereby activating PP2A and leading to dephosphorylation of MEK1/2 and ERK1/2. PHAPI knockdown by RNAi abolished both PP2A activation and MEK inhibition by jacalin.\",\n      \"method\": \"Immunoprecipitation kinase assays, PP2A activity assay, siRNA knockdown, Western blot of MEK/ERK phosphorylation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, phosphatase activity assay, and RNAi functional validation, single lab\",\n      \"pmids\": [\"15247276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ANP32A (I1PP2A) associates with the catalytic subunit of PP1 in the presence of Mn2+ and modifies its substrate specificity, stimulating PP1 activity toward myelin basic protein and histone H1 (but not phosphorylase) by 15–20 fold, an activity not seen with Co2+, Mg2+, Ca2+, or Zn2+.\",\n      \"method\": \"In vitro phosphatase activity assay, gel filtration co-elution with Mn2+, recombinant proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro reconstitution with purified recombinant proteins and multiple substrate tests\",\n      \"pmids\": [\"10734057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of the N-terminal LRR domain of pp32 (ANP32A) was determined, revealing a capped leucine-rich repeat fold that mediates protein-protein interactions characteristic of the ANP32 family.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure, single lab, validated by subsequent higher-resolution structures\",\n      \"pmids\": [\"17567741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ANP32A (pp32/LANP) interacts with adenovirus E4orf6, which exports pp32 from the nucleus to the cytoplasm along with HuR; this complex stabilizes ARE-containing mRNAs (c-fos, c-myc, COX-2) in the cytoplasm via a CRM1-independent mechanism.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, mRNA stability assays, CRM1 inhibitor (leptomycin B) experiments\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional mRNA assays in single lab\",\n      \"pmids\": [\"15983058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Adenovirus protein VII associates with ANP32A (pp32) and SET in vitro, with distinct protein VII domains responsible for binding each; protein VII, ANP32A, and SET co-associate with viral DNA during early infection.\",\n      \"method\": \"In vitro binding assays, chromatin immunoprecipitation, immunofluorescence\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding and ChIP, single lab\",\n      \"pmids\": [\"15681448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ANP32A (LANP) forms a complex with transcriptional repressor E4F and modulates its repressive activity; ataxin-1 competes with E4F for LANP binding, relieving LANP-E4F-mediated transcriptional repression. This links ANP32A to SCA1 pathology.\",\n      \"method\": \"Co-immunoprecipitation, transcriptional reporter assays, competition binding experiments\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus functional transcription assays, single lab\",\n      \"pmids\": [\"17557114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ANP32A (pp32) tumor suppression requires amino acids 150–174; deletion or truncation of this region abolishes inhibition of oncogene-mediated (RAS+MYC) transformation in rat embryo fibroblasts. The oncogenic pp32r1 and pp32r2 differ from pp32 precisely in this region.\",\n      \"method\": \"Deletion and truncation mutagenesis, rat embryo fibroblast transformation assays (focus formation, soft agar)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional mutagenesis in cell transformation assay, single lab\",\n      \"pmids\": [\"10400610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Hyperphosphorylated Rb interacts with ANP32A (pp32) but not with closely related pp32r1 or pp32r2; this Rb-pp32 interaction inhibits the apoptotic activity of pp32 and stimulates cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, apoptosis functional assays, proliferation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP with functional apoptosis and proliferation readouts, single lab\",\n      \"pmids\": [\"15716273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ANP32A (PHAPI) apoptotic activity—stimulation of caspase activation via the apoptosome—is required for its tumor suppressive function. The PHAPI close homolog pp32R1 (an oncoprotein) cannot stimulate caspase activation; the critical difference maps to amino acids in the caspase activation motif. ANP32A translocates from nucleus to cytoplasm during apoptosis; disruption of its NLS modestly decreases tumor suppression.\",\n      \"method\": \"Truncation mutagenesis, in vitro caspase activation assay, subcellular fractionation, tumor suppression assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple truncation mutants with in vitro caspase assay and localization studies, single lab\",\n      \"pmids\": [\"19121999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Sphingosine (and DMS, phytosphingosine) directly binds ANP32A identified by affinity chromatography/proteomics; sphingoid base binding relieves ANP32A-mediated PP2A inhibition in vitro and activates PP2A in endothelial cells, leading to p38 SAPK activation and COX-2 induction. ANP32A siRNA knockdown enhanced basal and DMS-activated PP2A activity.\",\n      \"method\": \"Affinity chromatography with sphingosine, proteomics, in vitro PP2A activity assay, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity chromatography plus in vitro PP2A assay and siRNA functional validation, single lab\",\n      \"pmids\": [\"20558741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ANP32A (LANP) depletion promotes neurite outgrowth in neuronal cell lines and primary neurons from LANP null mice; LANP directly binds the neurofilament light chain (NF-L) gene promoter and suppresses histone acetylation at this locus, repressing NF-L expression.\",\n      \"method\": \"siRNA knockdown in neuronal cell lines, primary neuron culture from LANP KO mice, ChIP at NF-L promoter, histone acetylation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse primary neurons + ChIP + functional phenotype, single lab\",\n      \"pmids\": [\"19136565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ANP32A (pp32) interacts with STAT1 and STAT2 in an IFN-dependent manner and is required for maximal transcriptional induction of IFN-stimulated genes (ISGs) by promoting assembly of transcription initiation complexes at ISG promoters; siRNA knockdown of pp32 reduces histone acetylation on ISG promoters.\",\n      \"method\": \"Co-immunoprecipitation (IFN-dependent), ChIP at ISG promoters, siRNA knockdown with IFN-stimulated gene expression readout\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + ChIP + functional siRNA, single lab\",\n      \"pmids\": [\"21325029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ANP32A (PP32) and SET/TAF-Iβ are components of the newly synthesized histone H4 complex identified by proteomics; they function to prevent HAT1-mediated acetylation of H4K5 and H4K12 in vitro. Depletion of PP32 and SET/TAF-Iβ causes hyperacetylation of H4 lysine residues, destabilizes H4-Hsp90 interaction, and results in S-phase arrest.\",\n      \"method\": \"Proteomic analysis of newly synthesized H4 complex, in vitro HAT inhibition assay, siRNA knockdown with histone acetylation and cell cycle analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics + in vitro HAT assay + siRNA functional readouts, single lab\",\n      \"pmids\": [\"28977641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ANP32A (pp32) overexpression in pancreatic cancer cells reduces HuR association with mRNAs encoding dCK, VEGF, and HuR itself; silencing pp32 enhances HuR binding to these mRNA targets, affecting gemcitabine sensitivity through altered dCK protein levels.\",\n      \"method\": \"RNA immunoprecipitation (RIP), overexpression and siRNA knockdown, mRNA binding assays, gemcitabine sensitivity assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RIP assay plus functional drug sensitivity readout, single lab\",\n      \"pmids\": [\"21152064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ANP32A deficiency in AML cells reduces genome-wide histone H3 acetylation, with significant H3 acetylation changes at lipid metabolism genes (APOC1, PCSK9, P2RX1, LPPR3); overexpression of APOC1 partially rescues the proliferation defect of ANP32A-deficient AML cells.\",\n      \"method\": \"Genome-wide ChIP-seq for H3 acetylation, gene expression analysis, APOC1 overexpression rescue experiment\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq plus functional rescue, single lab\",\n      \"pmids\": [\"29467488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ANP32A protects cartilage against oxidative stress and OA by promoting expression of ATM (a key cellular oxidative defense regulator); Anp32a-deficient mice show reduced ATM expression and develop OA, osteopenia, and cerebellar ataxia, all rescued by antioxidant treatment.\",\n      \"method\": \"Microarray profiling in Anp32a KO mice, in vivo OA model, antioxidant treatment, immunohistochemistry\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with transcriptome profiling and rescue experiment, single lab\",\n      \"pmids\": [\"30209244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ANP32A and ANP32B mediate nuclear export of unspliced/partially spliced HIV-1 mRNA via interactions with Rev and CRM1; double (but not single) knockout of ANP32A and ANP32B accumulates unspliced viral mRNA in the nucleus and reduces Gag protein expression; reconstitution of either restores viral production.\",\n      \"method\": \"Double knockout, RNA nuclear/cytoplasmic fractionation, co-immunoprecipitation with Rev and CRM1, Gag expression assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — double KO + Co-IP + reconstitution, single lab\",\n      \"pmids\": [\"31444273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Human ANP32A or ANP32B alone is indispensable for human influenza A virus RNA replication; two amino acids at positions 129–130 of chicken ANP32B are responsible for its inability to support viral replication and its weak interaction with the viral polymerase complex.\",\n      \"method\": \"siRNA/KO of ANP32A and ANP32B, polymerase activity reporter assays, co-immunoprecipitation, site-directed mutagenesis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO + polymerase assay + mutagenesis + Co-IP, single lab\",\n      \"pmids\": [\"30996088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Swine ANP32A uniquely (among mammalian ANP32 proteins) supports avian influenza polymerase activity; this is mapped to amino acids 106V and 156S in swANP32A. Mutation of these residues weakens interaction with chicken viral polymerase and reduces polymerase activity. ANP32A knockout in pig (PK15) cells dramatically reduces avian influenza polymerase activity.\",\n      \"method\": \"Polymerase activity reporter assays, site-directed mutagenesis, co-immunoprecipitation, ANP32A knockout in pig cells\",\n      \"journal\": \"PLoS pathogens / Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis + KO + Co-IP, replicated in two independent papers\",\n      \"pmids\": [\"32084248\", \"32269123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Downregulating ANP32A in hippocampal CA3 of tau transgenic mice rescues memory loss and synaptic deficits by reducing INHAT complex formation and unmasking histones for acetylation; ANP32A levels are upregulated by tau accumulation, β-amyloid, and H2O2 via C/EBPβ activation.\",\n      \"method\": \"Lentiviral shRNA stereotaxic injection, Morris water maze, electrophysiology, Golgi staining, ChIP, Western blot\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD with multiple functional readouts, single lab\",\n      \"pmids\": [\"28472990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ANP32A represses Wnt signaling in articular cartilage via histone acetylation masking; ANP32A co-immunoprecipitates with components at Wnt target gene loci, and its loss triggers Wnt hyper-activation and cardiac hypertrophy. Combined antioxidant and Wnt inhibitor treatment ameliorates OA in Anp32a-deficient mice.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-qPCR, luciferase assays, Anp32a KO mouse DMM OA model, Wnt inhibitor/antioxidant treatment\",\n      \"journal\": \"Osteoarthritis and cartilage\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + ChIP + KO mouse functional model, single lab\",\n      \"pmids\": [\"35227892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ANP32A (pp32) specifically binds to histone H3 and blocks both its acetylation and phosphorylation; pp32 overexpression inhibits cell growth in Jurkat T cells and directly initiates caspase activity and promotes granzyme A-mediated caspase-independent cell death.\",\n      \"method\": \"Histone binding assays, histone acetylation/phosphorylation analysis, caspase activity assay, cell growth assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct histone binding and caspase activation assays, single lab\",\n      \"pmids\": [\"16341127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ANP32A (LANP/I1PP2A) is pulled down by the cytoplasmic domain of integrin α3A and co-localizes with integrin α3β1; GST-ANP32A pulls down both integrin α3β1 and PP1 from cell lysates, and PP1 can dephosphorylate integrin α3β1 at T1046 in vitro, suggesting ANP32A bridges PP1 and integrin α3β1.\",\n      \"method\": \"Affinity chromatography, GST pulldown, co-localization by immunofluorescence, in vitro phosphatase assay\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pulldown and co-localization assays, functional bridge proposed but not fully established, single lab\",\n      \"pmids\": [\"17016859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The NMR solution structure of the ANP32A LRR domain was determined; the LRR domain interacts with the AXH domain of ataxin-1 with millimolar (very weak) affinity, suggesting additional partners or post-translational modification is needed for stable binding. Two-hybrid screening identified Clip-170/Restin as a new LRR domain partner.\",\n      \"method\": \"NMR spectroscopy, yeast two-hybrid screening, in vitro binding assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–3 / Moderate — NMR structure plus two-hybrid, weak affinity binding measured, single lab\",\n      \"pmids\": [\"18410380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Direct species-independent interactions exist between all ANP32A splice variants and the PB2 polymerase subunit; this interaction is enhanced in the presence of viral genomic RNA. However, only avian ANP32A (containing the 33-aa or 29-aa insertion) restored RNP complex assembly and enhanced RNA synthesis for a restricted polymerase.\",\n      \"method\": \"Split luciferase complementation assays, co-immunoprecipitation, influenza minigenome assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple interaction assays plus functional polymerase readout, single lab\",\n      \"pmids\": [\"30184493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Human ANP32A interacts weakly with influenza polymerase; the 33-aa insertion of avian ANP32A and a hydrophobic SIM-like sequence unique to avian ANP32A both promote stronger polymerase interaction. SUMOylation of the host cell contributes to vPol activity including avian ANP32A function.\",\n      \"method\": \"Split luciferase complementation, co-immunoprecipitation, in situ split Venus interaction, mutagenesis, SUMO pathway manipulation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple interaction assays + mutagenesis, single lab\",\n      \"pmids\": [\"28903035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ANP32A is required for both vRNA and cRNA synthesis by the influenza A virus polymerase (not just vRNA from cRNA as previously proposed); ANP32A is needed for the actively replicating polymerase but not the encapsidating polymerase.\",\n      \"method\": \"Minigenome assays with ANP32A knockout/rescue, virus infection studies, viral promoter mutations\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — minigenome assays plus KO functional analysis with promoter mutations, single lab\",\n      \"pmids\": [\"34935435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ANP32A (LANP/pp32) interacts with LIM-homeodomain transcription factor LHX3 via the LHX3 carboxyl terminus; LANP is associated with LHX3 target genes in pituitary cells (by ChIP), and experimental alteration of LANP levels affects LHX3-mediated pituitary gene regulation.\",\n      \"method\": \"Mass spectrometry, biochemical domain mapping, co-immunoprecipitation, ChIP, gain/loss-of-function transcription assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — MS identification + Co-IP + ChIP + functional assays, single lab\",\n      \"pmids\": [\"23861948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Human ANP32A is SUMOylated at K68 and K153 by the E3 SUMO ligase PIAS2α and deSUMOylated by SENP1; SUMOylated ANP32A recruits influenza NS2 via a SIM-SUMO interaction, facilitating ANP32A-supported avian polymerase activity and vRNP-ANP32A interactions.\",\n      \"method\": \"SUMOylation assays, mutagenesis of SUMOylation sites, co-immunoprecipitation, vRNP assembly assays, PIAS2α/SENP1 manipulation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SUMOylation site mutagenesis + Co-IP + functional vRNP assay, single lab\",\n      \"pmids\": [\"39737943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NMR characterization of ternary complexes shows avian ANP32A simultaneously binds influenza FluPol and NP via distinct linear motifs in its longer disordered domain; the 33-aa deletion in human ANP32A blocks this simultaneous colocalization. PB2-E627K mutation enables FluPol and NP to bind the same extended linear motif on human ANP32A in a highly dynamic multivalent ternary complex.\",\n      \"method\": \"NMR spectroscopy of ternary FluPol/NP/ANP32A complexes, interaction mapping\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural characterization of ternary complex with mechanistic interpretation, single lab\",\n      \"pmids\": [\"37707433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AIMP1 interacts with ANP32A (identified by protein chip assay) and this interaction regulates histone H3 acetylation in multiple myeloma cells; disruption of AIMP1 expression reduces H3 acetylation enrichment at GAREM2 locus and decreases ERK1/2 phosphorylation.\",\n      \"method\": \"Protein chip assay, co-immunoprecipitation, ChIP-seq, siRNA knockdown\",\n      \"journal\": \"Cancer communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — protein chip and Co-IP, mechanistic link to H3 acetylation suggested but limited functional validation of direct ANP32A mechanism\",\n      \"pmids\": [\"36042007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ANP32A (pp32) overexpression suppresses Raf-1 activation, downregulating ERK activation; the C-terminal half of pp32 is required for Raf-1 suppression. siRNA knockdown of pp32 enhances ERK and MEK activation.\",\n      \"method\": \"Overexpression and siRNA knockdown, Western blot of Raf-1/MEK/ERK phosphorylation, deletion mutagenesis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — KD/OE with phosphorylation readout, pathway placement not biochemically direct, single lab single method\",\n      \"pmids\": [\"16039954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cranial high-resolution X-ray crystal structure of the ANP32A LRR domain was determined at 1.56 Å, showing displacement in the turn connecting α1 to β1 compared to prior 2.4/2.69 Å structures.\",\n      \"method\": \"X-ray crystallography at 1.56 Å resolution\",\n      \"journal\": \"Acta crystallographica Section F\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — high-resolution crystal structure, single lab, structural refinement of known domain\",\n      \"pmids\": [\"26057796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ANP32A binds HMGA1 mRNA via RNA immunoprecipitation and maintains HMGA1 mRNA stability, thereby promoting HMGA1 protein expression and subsequent STAT3 activation in hepatocellular carcinoma cells.\",\n      \"method\": \"RNA immunoprecipitation (RIP), siRNA knockdown and overexpression, Western blot, xenograft model\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single RIP assay with functional readout, single lab, no direct binding mechanism established\",\n      \"pmids\": [\"33332531\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANP32A is a multifunctional nuclear phosphoprotein that acts as: (1) a potent endogenous inhibitor of PP2A (interacting specifically with its catalytic subunit) and a modifier of PP1 substrate specificity; (2) a core subunit of the INHAT complex that masks histones to inhibit acetyltransferases (p300/CBP, PCAF, HAT1) and repress transcription, with phosphorylation at Ser158/204 by casein kinase II regulating this activity; (3) a pro-apoptotic factor that, via its C-terminal LCAR domain, promotes apoptosome assembly by accelerating Apaf-1 nucleotide exchange (together with CAS and Hsp70) and facilitates cytoplasmic translocation of HuR for caspase-mediated cleavage; (4) an essential host cofactor for influenza A virus RNA polymerase, bridging two FluPol molecules via its LRR domain to form an asymmetric replication platform (cryo-EM structure established), with species-specific differences (a 33-aa avian-unique insertion in the LCAR) dictating which viral polymerase variants can be supported; and (5) a regulator of mRNA stability and nuclear export through interactions with HuR, CRM1, and Rev.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ANP32A is a small, leucine-rich-repeat nuclear phosphoprotein that integrates phosphatase regulation, chromatin acetylation control, apoptotic signaling, and host support of viral RNA replication [#0, #1, #3]. As a phosphatase regulator it is a potent and selective heat-stable inhibitor of PP2A, binding specifically the PP2A catalytic subunit through its N-terminal isotype-specific region [#0, #5], while in the presence of Mn2+ it associates with the PP1 catalytic subunit and redirects its substrate specificity [#12]; relief of PP2A inhibition by tyrosine phosphorylation or by direct binding of sphingoid bases links ANP32A to downstream MEK/ERK and p38 signaling [#11, #20], and its PP2A inhibition modulates Tau phosphorylation [#5]. In the nucleus ANP32A is a core subunit of the INHAT complex that binds unacetylated/hypoacetylated histones and masks them from acetyltransferases such as p300/CBP and PCAF, thereby repressing transcription [#1, #2]; this histone-masking activity is regulated by casein kinase II phosphorylation at Ser158/Ser204 [#6], operates on newly synthesized histone H4 to block HAT1-mediated acetylation [#23], and shapes acetylation-dependent programs governing neurofilament expression, interferon-stimulated genes, and lipid-metabolism loci [#21, #22, #25]. Through its C-terminal region ANP32A is pro-apoptotic and tumor-suppressive, promoting apoptosome assembly together with CAS and Hsp70 by accelerating Apaf-1 nucleotide exchange to enhance caspase-9 activation [#3], with the caspase-activating motif being required for both apoptotic and tumor-suppressor function [#17, #19]. ANP32A also controls mRNA fate, promoting cytoplasmic translocation and caspase cleavage of HuR during lethal stress and modulating HuR–mRNA association [#4, #24]. Finally, ANP32A (redundantly with ANP32B) is an essential host cofactor for influenza A virus polymerase: it interacts directly with the PB2 subunit, an interaction enhanced by viral RNA, and bridges two FluPol molecules into an asymmetric replication platform via its N-terminal LRR domain while its C-terminal disordered LCAR inserts between the juxtaposed PB2 627 domains [#8, #35, #37]. Species-specific support of avian polymerase is dictated by an avian-unique 33-amino-acid insertion in the disordered domain that restores multivalent binding lost with PB2-E627, explaining mammalian adaptation [#7, #10, #40]. Anp32a-deficient mice develop osteoarthritis, osteopenia and cerebellar ataxia linked to defective oxidative defense (reduced ATM) and Wnt de-repression, establishing physiological roles in tissue protection [#26, #31].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established ANP32A as a dedicated enzyme regulator by showing it is a selective, high-affinity inhibitor of PP2A, defining its first molecular activity.\",\n      \"evidence\": \"In vitro phosphatase assays with purified recombinant protein against PP2A, PP1, PP2B, PP2C\",\n      \"pmids\": [\"8679524\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural basis of PP2A selectivity\", \"Cellular consequences of PP2A inhibition not addressed\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Extended the phosphatase-regulatory repertoire by showing ANP32A modifies PP1 substrate specificity in a Mn2+-dependent manner, indicating it is not solely a PP2A inhibitor.\",\n      \"evidence\": \"In vitro phosphatase assays and gel filtration co-elution with recombinant proteins and multiple substrates\",\n      \"pmids\": [\"10734057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of Mn2+-dependence unclear\", \"No in vivo PP1 substrate identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined a chromatin function by identifying ANP32A as an INHAT subunit that masks histones to inhibit HATs, establishing transcriptional repression as a core role.\",\n      \"evidence\": \"In vitro HAT inhibition assays, transfection/colocalization, domain deletion mapping\",\n      \"pmids\": [\"11830591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide targets not defined at this stage\", \"Regulation of INHAT activity unaddressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Connected ANP32A histone masking to gene-specific repression and showed selectivity for hypoacetylated histones plus HDAC association, integrating it into the acetylation cycle.\",\n      \"evidence\": \"Histone binding assays, Co-IP with HDACs, ChIP at an estrogen-regulated gene; separate H3-binding/caspase study\",\n      \"pmids\": [\"15136563\", \"16341127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking histone state to recruitment unresolved\", \"Direct vs indirect HDAC association not separated\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified post-translational control of ANP32A by CKII phosphorylation at Ser158/Ser204, providing a regulatory switch over its functions.\",\n      \"evidence\": \"In vitro kinase assay, biochemical purification, site-directed mutagenesis, phospho-specific antibodies\",\n      \"pmids\": [\"15287743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which functions each phosphosite controls not fully mapped\", \"Upstream signals activating CKII on ANP32A unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established the pro-apoptotic mechanism by showing ANP32A accelerates Apaf-1 nucleotide exchange with CAS and Hsp70 to promote apoptosome assembly, and links ANP32A to HuR cytoplasmic translocation/cleavage.\",\n      \"evidence\": \"Apoptosome reconstitution, siRNA knockdown, HuR cleavage assays with non-cleavable mutant\",\n      \"pmids\": [\"18439902\", \"18180367\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How nuclear ANP32A reaches the cytoplasmic apoptosome not fully defined\", \"Trigger coupling apoptosis to HuR translocation incomplete\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapped the PP2A interaction to the N-terminal isotype-specific region and tied PP2A inhibition to a cellular readout (Tau phosphorylation), sharpening mechanism and function.\",\n      \"evidence\": \"GST pulldown, Co-IP, deletion mutagenesis, in vitro phosphatase assay, immunofluorescence\",\n      \"pmids\": [\"18245083\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the PP2Ac contact not resolved\", \"In vivo Tau relevance limited to overexpression model\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined ANP32A (with ANP32B) as host IREF-2 activity that engages free influenza RdRp and promotes vRNA synthesis, opening the viral-cofactor branch.\",\n      \"evidence\": \"Biochemical complementation with nuclear extracts, MS identification, siRNA knockdown\",\n      \"pmids\": [\"26512887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct polymerase contact not mapped here\", \"Step-specificity of replication not fully resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Explained the avian-to-mammalian host barrier by showing an avian-unique 33-aa insertion governs which polymerases ANP32A can support, establishing it as an essential, species-restricting host factor.\",\n      \"evidence\": \"Rescue, deletion/insertion mutagenesis, polymerase activity assays in mammalian cells\",\n      \"pmids\": [\"26738596\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic mechanism of the insertion's effect not yet defined\", \"Whether PB2-627 directly contacts ANP32A unresolved at this stage\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated functional redundancy of ANP32A/ANP32B for human influenza replication and extended ANP32 to HIV-1 unspliced mRNA nuclear export via Rev/CRM1.\",\n      \"evidence\": \"Single/double knockouts, polymerase reporter assays, RNA fractionation, Co-IP with Rev and CRM1, reconstitution\",\n      \"pmids\": [\"30996088\", \"31444273\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs scaffolding role in export not separated\", \"Tissue-level relevance of redundancy untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided structural mechanism: cryo-EM and NMR showed ANP32A bridges two FluPol via its LRR while the LCAR inserts between PB2 627 domains, explaining PB2-E627K mammalian adaptation through multivalent disordered-domain binding.\",\n      \"evidence\": \"Cryo-EM of FluPolC–ANP32A complexes; NMR of PB2 627-NLS/ANP32A complexes\",\n      \"pmids\": [\"33208942\", \"32694517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of the asymmetric dimer in cells not directly observed\", \"Generality across influenza A subtypes inferred from FluPolC\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Refined the host-range determinants, showing swine ANP32A residues (106V/156S) uniquely permit avian polymerase support and that SUMO/SIM-like features modulate polymerase interaction strength.\",\n      \"evidence\": \"Polymerase reporter assays, mutagenesis, Co-IP, ANP32A knockout in pig cells; split-luciferase interaction assays\",\n      \"pmids\": [\"32084248\", \"32269123\", \"28903035\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of each feature to replication not partitioned\", \"In vivo cross-species transmission impact not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revised the replication-step model by showing ANP32A is required for both vRNA and cRNA synthesis and specifically for the actively replicating, not encapsidating, polymerase.\",\n      \"evidence\": \"Minigenome assays with knockout/rescue, infection studies, promoter mutations\",\n      \"pmids\": [\"34935435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular distinction between replicating and encapsidating polymerase engagement unresolved\", \"Step-specific structural state not captured\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established physiological roles via knockout mice, linking ANP32A to oxidative defense (ATM) and acetylation-dependent gene programs in cartilage and leukemia.\",\n      \"evidence\": \"Anp32a KO mice, OA models, ChIP-seq for H3 acetylation, rescue experiments\",\n      \"pmids\": [\"30209244\", \"29467488\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect control of ATM/lipid genes not fully separated\", \"Tissue specificity of acetylation targets incomplete\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the multivalent ternary-complex logic, showing avian ANP32A simultaneously binds FluPol and NP through distinct linear motifs and that PB2-E627K rescues this on human ANP32A.\",\n      \"evidence\": \"NMR of FluPol/NP/ANP32A ternary complexes with interaction mapping\",\n      \"pmids\": [\"37707433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional output of NP co-recruitment in replication not quantified in cells\", \"Order of assembly events unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added a SUMO regulatory layer, showing PIAS2α-mediated SUMOylation at K68/K153 recruits influenza NS2 via SIM-SUMO contacts to facilitate avian polymerase support.\",\n      \"evidence\": \"SUMOylation assays, site mutagenesis, Co-IP, vRNP assembly assays, PIAS2α/SENP1 manipulation\",\n      \"pmids\": [\"39737943\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SUMOylation also regulates non-viral ANP32A functions untested\", \"Dynamics of SUMO cycling during infection unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ANP32A's multiple activities (phosphatase inhibition, histone masking, apoptosome promotion, viral polymerase support) are coordinated and switched within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking post-translational modifications to selection among competing functions\", \"Structural basis of PP2A and PP1 contacts unsolved\", \"Mechanism controlling nuclear-cytoplasmic redistribution across contexts undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5, 12, 11, 20]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [1, 2, 23, 32]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 21, 22]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 8, 35]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [9, 24, 35]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2, 19]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 14, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 2, 23]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 4, 19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 8, 9, 27]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 24, 27]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 11, 20]}\n    ],\n    \"complexes\": [\"INHAT complex\", \"apoptosome (Apaf-1)\", \"influenza FluPol replication platform\", \"newly synthesized histone H4 complex\"],\n    \"partners\": [\"PP2A catalytic subunit\", \"PP1\", \"HuR\", \"Apaf-1\", \"CRM1\", \"PB2 (influenza polymerase)\", \"CSNK2 (casein kinase II)\", \"ANP32B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win"}}