{"gene":"TP53INP2","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2008,"finding":"TP53INP2 binds to LC3, GABARAP, and GABARAPL2 (Atg8-family proteins) as well as the autophagosome transmembrane protein VMP1; it translocates from the nucleus to autophagosome structures upon autophagy induction by rapamycin or starvation; siRNA-mediated knockdown strongly decreases autophagosome formation, indicating TP53INP2 is required for autophagy; it is proposed to act as a scaffold recruiting LC3/GABARAP to the autophagosome membrane via VMP1.","method":"Yeast two-hybrid screening, co-immunoprecipitation, siRNA knockdown, bioluminescence resonance energy transfer (BRET), fluorescence microscopy","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, BRET, siRNA KD with defined autophagy phenotype, replicated by multiple orthogonal methods in one rigorous study","pmids":["19056683"],"is_preprint":false},{"year":2012,"finding":"Structure-function analysis identified two conserved regions in DOR/TP53INP2: region 1 (aa 28–42) contains a nuclear export signal (NES) and a functional LC3-interacting region (LIR) motif; mutations in hydrophobic residues of region 1 reduce transcriptional activity and block nuclear exit and autophagic activity. Region 2 (aa 66–112) mutations reduce transcriptional activity, impair nuclear exit upon autophagy activation, and disrupt autophagy. TP53INP1 arose by gene duplication in vertebrates and also regulates autophagy and transcription.","method":"Phylogenetic reconstruction, structure/function mutagenesis, nuclear export and transcriptional activity assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mutagenesis of specific residues with multiple functional readouts (transcription, nuclear localization, autophagy) in a single focused study","pmids":["22470510"],"is_preprint":false},{"year":2014,"finding":"Muscle-specific overexpression of Tp53inp2 in transgenic mice reduces muscle mass, while Tp53inp2 deletion causes muscle hypertrophy. TP53INP2 activates basal autophagy in skeletal muscle and sustains p62-independent autophagic degradation of ubiquitinated proteins. TP53INP2 ablation mitigates experimental diabetes-associated muscle loss, and its overexpression/absence does not affect denervation-induced wasting (where autophagy is blocked), placing TP53INP2 specifically upstream of autophagy-dependent muscle mass regulation.","method":"Transgenic mouse models (muscle-specific overexpression and knockout), streptozotocin-induced diabetes model, denervation model, autophagy flux assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo genetic models with defined phenotypic readouts and epistasis via denervation control, replicated across conditions","pmids":["24713655"],"is_preprint":false},{"year":2016,"finding":"TP53INP2 localizes to the nucleolus via a C-terminal nucleolar localization signal (NoLS). ChIP assays detect TP53INP2 association with ribosomal DNA (rDNA). Exclusion of TP53INP2 from the nucleolus represses rDNA promoter activity and reduces rRNA and ribosomal protein production. TP53INP2 directly interacts with and is required for assembly of the POLR1/RNA polymerase I preinitiation complex (PIC) at rDNA promoters, revealing a role in promoting ribosome biogenesis.","method":"Chromatin immunoprecipitation (ChIP), nucleolar localization assays, RNA polymerase I PIC interaction and assembly assays, rRNA production measurements","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP, direct interaction assays, and functional promoter activity readouts in one study with multiple orthogonal methods","pmids":["27172002"],"is_preprint":false},{"year":2018,"finding":"TP53INP2 negatively regulates adipogenesis in preadipocytes by promoting autophagy-dependent sequestration of GSK3β into late endosomes in an ESCRT-dependent manner. This sequestration increases β-catenin levels and enhances TCF/LEF transcriptional activity. TP53INP2 ablation in mice causes enhanced adiposity with greater cellularity of subcutaneous adipose tissue and increased expression of adipogenic master genes.","method":"Transgenic mouse models (TP53INP2 knockout), preadipocyte differentiation assays, late endosome fractionation, β-catenin/TCF-LEF reporter assays, ESCRT inhibition experiments","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout phenotype, mechanistic pathway dissection via endosomal fractionation and reporter assays, ESCRT dependency established","pmids":["29593329"],"is_preprint":false},{"year":2019,"finding":"TP53INP2 sensitizes cells to death receptor-induced apoptosis by binding both caspase-8 and the ubiquitin ligase TRAF6, functioning as a scaffold that bridges ubiquitinated caspase-8 to TRAF6 for further polyubiquitination and activation of caspase-8. A TRAF6-interacting motif (TIM) and a ubiquitin-interacting motif (UIM) in TP53INP2 are required; mutations of key TIM residues abrogate TRAF6 and caspase-8 interaction and reduce death receptor-induced apoptosis. TP53INP2 deficiency in cultured cells or mouse livers protects against death receptor-induced apoptosis.","method":"Co-immunoprecipitation, site-directed mutagenesis of TIM and UIM motifs, in vivo mouse liver apoptosis model, apoptosis assays with TRAIL/FasL","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, mutagenesis of defined motifs, in vivo liver model, multiple orthogonal methods in one rigorous study","pmids":["30979779"],"is_preprint":false},{"year":2019,"finding":"Cytoplasmic TP53INP2 promotes autophagosome biogenesis by directly interacting with ATG7 to form a LC3B-TP53INP2-ATG7 ternary complex. The N-terminal region of TP53INP2 (including the LIR) is sufficient to trigger LC3B-PE lipidation and autophagosome formation. Loss of TP53INP2-LC3 or TP53INP2-ATG7 interaction significantly reduces LC3B-ATG7 binding. TP53INP2 colocalizes with early autophagic membrane structures (ATG14, DFCP1, WIPI2-positive).","method":"Co-immunoprecipitation, GST pulldown, LIR mutant analysis (W35A/I38A), autophagosome formation assays, fluorescence colocalization, LC3B-PE lipidation assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, mutagenesis, lipidation assay, colocalization, multiple orthogonal methods confirming direct TP53INP2-ATG7 interaction and functional consequence","pmids":["30767704"],"is_preprint":false},{"year":2019,"finding":"TP53INP2 contains a ubiquitin-interacting motif (UIM) that mediates binding to ubiquitin and ubiquitinated proteins. TP53INP2 lacking the UIM can displace the autophagic adaptor p62 from LC3, leading to accumulation of ubiquitinated proteins; overexpression of UIM-deficient TP53INP2 sensitizes cells to chloroquine. This indicates TP53INP2 can act as a novel autophagic adaptor recruiting ubiquitinated substrates to autophagosomes.","method":"UIM domain deletion mutagenesis, ubiquitin binding assays, co-immunoprecipitation, autophagy flux assays, chloroquine sensitivity assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — mutagenesis and pulldown in a single lab study, functional consequences shown but single paper","pmids":["31155706"],"is_preprint":false},{"year":2009,"finding":"hnRNP A2 controls alternative splicing of an exon in the 5' UTR of TP53INP2 in a 3D matrix-dependent fashion; this splicing event is required for invasive cell migration into extracellular matrix, with consequences mediated via alterations in Golgi complex integrity during 3D migration.","method":"siRNA knockdown of hnRNP A2, exon-tiling microarrays, 3D matrix invasion assays, Golgi morphology analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — exon-tiling arrays plus functional invasion assay and Golgi readout, single lab but two orthogonal approaches","pmids":["19934309"],"is_preprint":false},{"year":2023,"finding":"FTO-mediated m6A demethylation upregulates TP53INP2 expression in NPM1-mutated AML cells. Mutant NPM1 directly interacts with TP53INP2 and delocalizes it to the cytoplasm. Cytoplasmic TP53INP2 then enhances autophagy by promoting LC3-ATG7 interaction, facilitating leukemia cell survival.","method":"Co-immunoprecipitation (TP53INP2 with mutant NPM1), m6A modification assays (FTO), LC3-ATG7 interaction assays, gain/loss-of-function in AML cells","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and functional assays in a single lab, mechanistic linkage across FTO→TP53INP2→LC3/ATG7 supported by multiple experiments","pmids":["36675134"],"is_preprint":false},{"year":2024,"finding":"TP53INP2 is predominantly degraded by nuclear proteasomes under basal conditions. Under starvation or chemical stress, TP53INP2 accumulates in the cytoplasm independently of ATG5, CRM1-mediated export, phosphorylation, ubiquitylation, or acetylation. A C-terminal nuclear localization signal (NLS) overlapping a nucleolar localization signal (NoLS) mediates nuclear import and nucleolar enrichment; a conserved nine-amino-acid cytoplasmic retention motif (CRM) in the C-terminus prevents nuclear re-entry under stress. FRAP and importin-binding assays show starvation disrupts nuclear import. Starvation also enhances TP53INP2 translation via FTO-mediated m6A demethylation without altering mRNA stability.","method":"CRISPR/Cas9 knockout + EGFP-TP53INP2 reconstitution, deletion mutagenesis, FRAP, importin-binding assays, proteasome inhibitor experiments, ATG5 KO epistasis, m6A/FTO assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — FRAP, importin binding, CRISPR reconstitution, mutagenesis of NLS/NoLS/CRM, and epistasis all in one study with multiple rigorous orthogonal methods","pmids":["41368677"],"is_preprint":false},{"year":2024,"finding":"The TP53INP2 LIR motif binds preferentially to GABARAP subfamily proteins over LC3 subfamily proteins. Crystal structures of TP53INP2LIR complexes with GABARAP and LC3A (acetylated and deacetylated) reveal a β-sheet interaction in TP53INP2LIR that determines GABARAP selectivity. Acetylation of the second conserved Lys residue (K49 in LC3B equivalent) in GABARAP or LC3A disrupts interaction with TP53INP2 and impairs nuclear/cytoplasmic LC3 shuttling in cells.","method":"Isothermal titration calorimetry (ITC), X-ray crystallography (crystal structures of TP53INP2LIR-GABARAP and TP53INP2LIR-LC3A complexes), acetyl-mimetic mutant cell assays, colocalization studies","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures plus ITC biophysics plus cell-based validation with mutagenesis, multiple orthogonal methods in one study","pmids":["38726830"],"is_preprint":false},{"year":2025,"finding":"TP53INP2 localizes predominantly to mitochondria in dedifferentiated liposarcoma cells and promotes mitophagic degradation of YAP in a VDAC1-dependent manner. The WW domain of YAP and the PPTY motif of VDAC1 are required for YAP-VDAC1 interaction. TP53INP2 gain/loss-of-function experiments show it inhibits proliferation, migration, stemness, and dedifferentiation of DDLPS cells.","method":"Subcellular fractionation/mitochondrial localization, gain/loss-of-function in DDLPS cell lines, domain mutant analysis (WW domain, PPTY motif), mitophagy assays, YAP protein level/activity measurements","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — mitochondrial localization shown, domain mutagenesis, and functional phenotype, but single lab, single paper","pmids":["40185868"],"is_preprint":false},{"year":2025,"finding":"In mature adipocytes, TP53INP2 acts as an adaptor protein for lipophagy by directly binding to lipid droplet-associated protein perilipin 1 (PLIN1) and to LC3 via its LIR motif. Co-IP confirmed TP53INP2-PLIN1 interaction. TP53INP2 knockdown impairs lipophagy and prevents PLIN1 degradation, even though general autophagy (p62-LC3) continues, indicating selective lipophagy adaptor function.","method":"Co-immunoprecipitation (TP53INP2-PLIN1, TP53INP2-LC3), siRNA knockdown, lipophagy flux assays in 3T3L1 cells, starvation induction","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — Co-IP and siRNA KD in a single lab, single paper; novel finding but limited orthogonal validation","pmids":["40484366"],"is_preprint":false},{"year":2021,"finding":"Oxidative stress-induced downregulation of TP53INP2 in BMSCs is mediated by the autophagy-lysosome degradation pathway, as autophagy inhibition with bafilomycin A1 rescues TP53INP2 protein levels. TP53INP2 knockdown inhibits osteogenic differentiation of BMSCs while overexpression promotes it, acting through activation of Wnt/β-catenin signaling (DKK1 abrogated and lithium rescued these effects).","method":"siRNA knockdown, overexpression, bafilomycin A1 treatment, Wnt/β-catenin pathway assays, osteogenic differentiation assays in BMSCs and OVX mouse model","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function with pathway rescue using DKK1 and lithium, in vitro and in vivo, single lab","pmids":["33636337"],"is_preprint":false},{"year":2023,"finding":"ZSCAN18 functions as a transcription factor that binds the TP53INP2 promoter and transcriptionally activates TP53INP2 expression in gastric cancer cells. Knockdown of TP53INP2 alleviates the tumor-suppressive effects of ZSCAN18 overexpression, placing TP53INP2 downstream of ZSCAN18 in an autophagy-promoting tumor-suppressive axis.","method":"Chromatin immunoprecipitation (ChIP) for ZSCAN18 at TP53INP2 promoter, epistasis by TP53INP2 siRNA knockdown in ZSCAN18-overexpressing cells, in vitro and in vivo tumor assays","journal":"Clinical epigenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus genetic epistasis, single lab with two orthogonal methods","pmids":["36650573"],"is_preprint":false},{"year":2024,"finding":"Cytoplasmic TP53INP2 (maintained by mutant NPM1) functions as a scaffold bridging TRAF6 to caspase-8, promoting caspase-8 ubiquitination and activation via the extrinsic apoptosis pathway in AML cells with NPM1 mutations. This was confirmed by co-immunoprecipitation and ubiquitination assays in gain/loss-of-function experiments.","method":"Co-immunoprecipitation, ubiquitination assays, gain/loss-of-function experiments, CDX and PDX mouse models, flow cytometry for apoptosis","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo PDX model, single lab, consistent with prior EMBO Journal data","pmids":["38909249"],"is_preprint":false}],"current_model":"TP53INP2/DOR is a multifunctional scaffold protein that acts as a sensor of nutrient status: under basal conditions it resides in the nucleus (where it is degraded by nuclear proteasomes) and nucleolus (where it promotes rDNA transcription by facilitating RNA Pol I preinitiation complex assembly), but upon starvation or stress it accumulates in the cytoplasm via a conserved cytoplasmic retention motif (CRM) and disrupted importin-mediated nuclear import; in the cytoplasm it promotes autophagosome biogenesis by binding deacetylated Atg8-family proteins (preferentially GABARAP subfamily) through its LIR motif and by scaffolding an LC3B–TP53INP2–ATG7 complex that promotes LC3 lipidation, while its ubiquitin-interacting motif (UIM) enables recruitment of ubiquitinated cargo to autophagosomes; independently, TP53INP2 sensitizes cells to death receptor-induced apoptosis by bridging TRAF6 to caspase-8 for polyubiquitination and activation; it also regulates adipogenesis and muscle mass through autophagy-dependent sequestration of GSK3β into late endosomes (activating β-catenin) and promotes lipophagy in mature adipocytes by binding perilipin 1."},"narrative":{"mechanistic_narrative":"TP53INP2 (DOR) is a nutrient-responsive scaffold protein that couples subcellular localization to dual roles in ribosome biogenesis and autophagy [PMID:19056683, PMID:27172002, PMID:41368677]. Under basal conditions it is imported into the nucleus and nucleolus via a C-terminal NLS/NoLS, where nuclear proteasomes degrade most of the pool and where it associates with rDNA and is required for assembly of the RNA polymerase I preinitiation complex, thereby promoting rRNA synthesis and ribosome biogenesis [PMID:27172002, PMID:41368677]. Upon starvation or stress, disrupted importin-mediated import together with a conserved C-terminal cytoplasmic retention motif drives cytoplasmic accumulation, an event independent of CRM1 export, ubiquitylation, or acetylation and reinforced by FTO-mediated m6A demethylation that enhances its translation [PMID:41368677]. In the cytoplasm TP53INP2 functions as a positive regulator of autophagosome biogenesis: it binds Atg8-family proteins through a LIR motif with structural preference for the GABARAP subfamily, an interaction abrogated by acetylation of a conserved Atg8 lysine, and it directly engages ATG7 to form an LC3B–TP53INP2–ATG7 ternary complex that promotes LC3 lipidation and autophagosome formation [PMID:19056683, PMID:30767704, PMID:38726830]. Its ubiquitin-interacting motif allows recruitment of ubiquitinated cargo, enabling p62-independent autophagic degradation, a function confirmed in skeletal muscle where TP53INP2 controls muscle mass through autophagy-dependent protein degradation [PMID:24713655, PMID:31155706]. As a selective adaptor it also mediates lipophagy by bridging perilipin 1 to LC3 in adipocytes and regulates adipogenesis by promoting autophagy- and ESCRT-dependent sequestration of GSK3β into late endosomes to activate β-catenin/TCF-LEF signaling [PMID:29593329, PMID:40484366]. Independently of autophagy, TP53INP2 sensitizes cells to death receptor–induced apoptosis by acting as a scaffold that bridges ubiquitinated caspase-8 to the ligase TRAF6 via dedicated TRAF6-interacting (TIM) and ubiquitin-interacting (UIM) motifs, promoting caspase-8 polyubiquitination and activation [PMID:30979779].","teleology":[{"year":2008,"claim":"Established TP53INP2 as a required factor for autophagy that physically links the Atg8 conjugation machinery to autophagosome membranes, defining its core cellular role.","evidence":"Yeast two-hybrid, reciprocal Co-IP, BRET, siRNA knockdown with autophagosome quantification, and microscopy in mammalian cells","pmids":["19056683"],"confidence":"High","gaps":["Did not resolve which LIR residues mediate Atg8 binding","Mechanism of nucleus-to-autophagosome relocalization unknown","VMP1-dependence not structurally defined"]},{"year":2012,"claim":"Mapped the functional architecture, identifying a region containing an NES and a LIR motif and a second conserved region, both required for nuclear exit, transcriptional activity, and autophagy, linking localization control to dual function.","evidence":"Phylogenetic reconstruction plus structure/function mutagenesis with transcription, nuclear export, and autophagy readouts","pmids":["22470510"],"confidence":"High","gaps":["Transcriptional targets not defined at this stage","Structural basis of LIR-Atg8 selectivity not addressed","Did not distinguish import vs export contributions"]},{"year":2014,"claim":"Demonstrated in vivo that TP53INP2 controls skeletal muscle mass specifically through autophagy-dependent, p62-independent degradation of ubiquitinated proteins, establishing physiological relevance.","evidence":"Muscle-specific transgenic overexpression and knockout mice, diabetes and denervation models, autophagy flux assays","pmids":["24713655"],"confidence":"High","gaps":["Cargo-recognition mechanism for ubiquitinated proteins not yet molecularly defined","Upstream signals controlling muscle TP53INP2 activity unclear"]},{"year":2016,"claim":"Revealed a nuclear/nucleolar function distinct from autophagy: TP53INP2 promotes ribosome biogenesis by associating with rDNA and enabling RNA Pol I preinitiation complex assembly.","evidence":"ChIP at rDNA, nucleolar localization assays, Pol I PIC interaction/assembly assays, rRNA measurements","pmids":["27172002"],"confidence":"High","gaps":["Direct contacts within the Pol I PIC not structurally mapped","How nutrient state toggles between nucleolar and autophagic pools not resolved here"]},{"year":2018,"claim":"Connected TP53INP2 to adipogenesis through autophagy- and ESCRT-dependent sequestration of GSK3β into late endosomes, linking it to β-catenin/TCF-LEF transcriptional control.","evidence":"Knockout mice, preadipocyte differentiation, late-endosome fractionation, β-catenin/TCF-LEF reporters, ESCRT inhibition","pmids":["29593329"],"confidence":"High","gaps":["Direct GSK3β-TP53INP2 binding interface not defined","How ESCRT and autophagy machineries cooperate mechanistically unclear"]},{"year":2019,"claim":"Defined an autophagy-independent apoptotic function: TP53INP2 scaffolds TRAF6 and caspase-8 via TIM and UIM motifs to drive caspase-8 polyubiquitination and death receptor sensitivity.","evidence":"Reciprocal Co-IP, TIM/UIM mutagenesis, in vivo mouse liver apoptosis model, TRAIL/FasL assays","pmids":["30979779"],"confidence":"High","gaps":["Ubiquitin chain type on caspase-8 not characterized","How apoptotic vs autophagic functions are partitioned not resolved"]},{"year":2019,"claim":"Resolved the autophagosome-biogenesis mechanism by showing TP53INP2 directly binds ATG7 to form an LC3B–TP53INP2–ATG7 ternary complex sufficient to trigger LC3 lipidation.","evidence":"Co-IP, GST pulldown, LIR mutant (W35A/I38A), LC3B-PE lipidation assays, colocalization with ATG14/DFCP1/WIPI2","pmids":["30767704"],"confidence":"High","gaps":["Stoichiometry and structure of the ternary complex not determined","Whether ATG7 binding is direct at the same surface as LC3 unresolved"]},{"year":2019,"claim":"Proposed TP53INP2 as a ubiquitin-binding autophagic adaptor via its UIM, capable of competing with p62 for LC3 and routing ubiquitinated cargo.","evidence":"UIM deletion mutagenesis, ubiquitin-binding assays, Co-IP, autophagy flux and chloroquine sensitivity assays","pmids":["31155706"],"confidence":"Medium","gaps":["Single-lab study without reciprocal in vivo validation","Endogenous ubiquitinated substrates not identified","Relationship to p62 in physiological contexts unclear"]},{"year":2024,"claim":"Defined the localization switch: a C-terminal NLS/NoLS drives import and nucleolar enrichment, while a conserved CRM blocks nuclear re-entry under stress, with starvation disrupting importin-mediated import to enforce cytoplasmic accumulation.","evidence":"CRISPR knockout/EGFP reconstitution, deletion mutagenesis, FRAP, importin-binding assays, proteasome inhibition, ATG5-KO epistasis, m6A/FTO assays","pmids":["41368677"],"confidence":"High","gaps":["The sensor that converts starvation into impaired import not identified","How CRM mechanistically blocks re-entry not structurally defined"]},{"year":2024,"claim":"Provided the structural and biophysical basis for GABARAP-subfamily selectivity and showed Atg8 acetylation acts as a switch controlling TP53INP2 binding and shuttling.","evidence":"ITC, X-ray crystal structures of TP53INP2-LIR with GABARAP and acetylated/deacetylated LC3A, acetyl-mimetic mutant cell assays","pmids":["38726830"],"confidence":"High","gaps":["The acetyltransferase/deacetylase regulating Atg8 K49 in this context not identified","Functional consequence of selectivity for specific cargo not dissected"]},{"year":null,"claim":"Multiple tissue- and cancer-context functions (NPM1-mutant AML survival and apoptosis, gastric cancer ZSCAN18 axis, BMSC osteogenesis, DDLPS mitophagy of YAP, adipocyte lipophagy via PLIN1) remain to be integrated into a unified regulatory logic for how TP53INP2's localization and partner choice are selected in each setting.","evidence":"Multiple single-lab cancer and differentiation studies","pmids":[],"confidence":"Low","gaps":["Context-specific upstream regulators largely uncharacterized","Mitochondrial localization and VDAC1-dependent mitophagy of YAP rest on a single study","Lipophagy adaptor role via PLIN1 not independently confirmed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,6,13]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,3]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[3,10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,10]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,2,6]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4]}],"complexes":["LC3B-TP53INP2-ATG7 complex"],"partners":["LC3B","GABARAP","GABARAPL2","ATG7","TRAF6","CASP8","PLIN1","VMP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IXH6","full_name":"Tumor protein p53-inducible nuclear protein 2","aliases":["Diabetes and obesity-regulated gene","p53-inducible protein U","PIG-U"],"length_aa":220,"mass_kda":24.0,"function":"Dual regulator of transcription and autophagy. Positively regulates autophagy and is required for autophagosome formation and processing. May act as a scaffold protein that recruits MAP1LC3A, GABARAP and GABARAPL2 and brings them to the autophagosome membrane by interacting with VMP1 where, in cooperation with the BECN1-PI3-kinase class III complex, they trigger autophagosome development. Acts as a transcriptional activator of THRA","subcellular_location":"Cytoplasm, cytosol; Nucleus; Nucleus, PML body; Cytoplasmic vesicle, autophagosome","url":"https://www.uniprot.org/uniprotkb/Q8IXH6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TP53INP2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RACK1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TP53INP2","total_profiled":1310},"omim":[{"mim_id":"617549","title":"TUMOR PROTEIN p53-INDUCIBLE NUCLEAR PROTEIN 2; TP53INP2","url":"https://www.omim.org/entry/617549"},{"mim_id":"600124","title":"HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN A2/B1; HNRNPA2B1","url":"https://www.omim.org/entry/600124"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":888.0}],"url":"https://www.proteinatlas.org/search/TP53INP2"},"hgnc":{"alias_symbol":["FLJ21759","FLJ23500","DKFZp434B2411","DKFZp434O0827","dJ1181N3.1","PINH","DOR"],"prev_symbol":["C20orf110"]},"alphafold":{"accession":"Q8IXH6","domains":[{"cath_id":"1.20.5","chopping":"166-194","consensus_level":"medium","plddt":92.6938,"start":166,"end":194}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IXH6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IXH6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IXH6-F1-predicted_aligned_error_v6.png","plddt_mean":63.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TP53INP2","jax_strain_url":"https://www.jax.org/strain/search?query=TP53INP2"},"sequence":{"accession":"Q8IXH6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IXH6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IXH6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IXH6"}},"corpus_meta":[{"pmid":"19056683","id":"PMC_19056683","title":"The TP53INP2 protein is required for autophagy in mammalian cells.","date":"2008","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/19056683","citation_count":108,"is_preprint":false},{"pmid":"24713655","id":"PMC_24713655","title":"Autophagy-regulating TP53INP2 mediates muscle wasting and is repressed in diabetes.","date":"2014","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/24713655","citation_count":73,"is_preprint":false},{"pmid":"19934309","id":"PMC_19934309","title":"hnRNP A2 regulates alternative mRNA splicing of TP53INP2 to control invasive cell migration.","date":"2009","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/19934309","citation_count":69,"is_preprint":false},{"pmid":"30767704","id":"PMC_30767704","title":"TP53INP2 contributes to autophagosome formation by promoting LC3-ATG7 interaction.","date":"2019","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/30767704","citation_count":68,"is_preprint":false},{"pmid":"33636337","id":"PMC_33636337","title":"Oxidative stress induces downregulation of TP53INP2 and suppresses osteogenic differentiation of BMSCs during osteoporosis through the autophagy degradation pathway.","date":"2021","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33636337","citation_count":68,"is_preprint":false},{"pmid":"29593329","id":"PMC_29593329","title":"TP53INP2 regulates adiposity by activating β-catenin through autophagy-dependent sequestration of GSK3β.","date":"2018","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/29593329","citation_count":57,"is_preprint":false},{"pmid":"22470510","id":"PMC_22470510","title":"DOR/Tp53inp2 and Tp53inp1 constitute a metazoan gene family encoding dual regulators of autophagy and transcription.","date":"2012","source":"PloS 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Expression of TP53INP2 Modulated by Demethylase FTO and Mutant NPM1 Promotes Autophagy in Leukemia Cells.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36675134","citation_count":21,"is_preprint":false},{"pmid":"33061441","id":"PMC_33061441","title":"TP53INP2 Modulates Epithelial-to-Mesenchymal Transition via the GSK-3β/β-Catenin/Snail1 Pathway in Bladder Cancer Cells.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33061441","citation_count":20,"is_preprint":false},{"pmid":"38545813","id":"PMC_38545813","title":"TP53INP2-dependent activation of muscle autophagy ameliorates sarcopenia and promotes healthy aging.","date":"2024","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/38545813","citation_count":17,"is_preprint":false},{"pmid":"19145107","id":"PMC_19145107","title":"TP53INP2 is the new guest at the table of 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Cancer via Caspase-8/TRAF6 Signaling Pathway.","date":"2022","source":"Journal of immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/35615533","citation_count":11,"is_preprint":false},{"pmid":"32535070","id":"PMC_32535070","title":"Dysregulation in the expression of (lncRNA-TSIX, TP53INP2 mRNA, miRNA-1283) in spinal cord injury.","date":"2020","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/32535070","citation_count":11,"is_preprint":false},{"pmid":"31810209","id":"PMC_31810209","title":"TP53INP2 Promotes Bovine Adipocytes Differentiation Through Autophagy Activation.","date":"2019","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/31810209","citation_count":11,"is_preprint":false},{"pmid":"35954230","id":"PMC_35954230","title":"TP53INP2 Contributes to TGF-β2-Induced Autophagy during the Epithelial-Mesenchymal Transition in Posterior Capsular Opacification 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CR","url":"https://pubmed.ncbi.nlm.nih.gov/38909249","citation_count":6,"is_preprint":false},{"pmid":"31528702","id":"PMC_31528702","title":"TP53INP2 at the crossroad of apoptosis and autophagy in death receptor signaling.","date":"2019","source":"Molecular & cellular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31528702","citation_count":6,"is_preprint":false},{"pmid":"22995226","id":"PMC_22995226","title":"Extrinsic and intrinsic regulation of DOR/TP53INP2 expression in mice: effects of dietary fat content, tissue type and sex in adipose and muscle tissues.","date":"2012","source":"Nutrition & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/22995226","citation_count":6,"is_preprint":false},{"pmid":"33897760","id":"PMC_33897760","title":"Integrative Analysis of TP53INP2 in Head and Neck Squamous Cell Carcinoma.","date":"2021","source":"Frontiers in 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biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/39614944","citation_count":1,"is_preprint":false},{"pmid":"40185868","id":"PMC_40185868","title":"TP53INP2 promotes mitophagic degradation of YAP to impede dedifferentiated liposarcoma development.","date":"2025","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/40185868","citation_count":0,"is_preprint":false},{"pmid":"41368677","id":"PMC_41368677","title":"A C-terminal cytoplasmic retention motif and nuclear localization signal regulates nuclear import of TP53INP2.","date":"2025","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/41368677","citation_count":0,"is_preprint":false},{"pmid":"38726830","id":"PMC_38726830","title":"Structural and functional characterization of the role of acetylation on the interactions of the human Atg8-family proteins with the autophagy receptor 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GABARAPL2 (Atg8-family proteins) as well as the autophagosome transmembrane protein VMP1; it translocates from the nucleus to autophagosome structures upon autophagy induction by rapamycin or starvation; siRNA-mediated knockdown strongly decreases autophagosome formation, indicating TP53INP2 is required for autophagy; it is proposed to act as a scaffold recruiting LC3/GABARAP to the autophagosome membrane via VMP1.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, siRNA knockdown, bioluminescence resonance energy transfer (BRET), fluorescence microscopy\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, BRET, siRNA KD with defined autophagy phenotype, replicated by multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"19056683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Structure-function analysis identified two conserved regions in DOR/TP53INP2: region 1 (aa 28–42) contains a nuclear export signal (NES) and a functional LC3-interacting region (LIR) motif; mutations in hydrophobic residues of region 1 reduce transcriptional activity and block nuclear exit and autophagic activity. Region 2 (aa 66–112) mutations reduce transcriptional activity, impair nuclear exit upon autophagy activation, and disrupt autophagy. TP53INP1 arose by gene duplication in vertebrates and also regulates autophagy and transcription.\",\n      \"method\": \"Phylogenetic reconstruction, structure/function mutagenesis, nuclear export and transcriptional activity assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of specific residues with multiple functional readouts (transcription, nuclear localization, autophagy) in a single focused study\",\n      \"pmids\": [\"22470510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Muscle-specific overexpression of Tp53inp2 in transgenic mice reduces muscle mass, while Tp53inp2 deletion causes muscle hypertrophy. TP53INP2 activates basal autophagy in skeletal muscle and sustains p62-independent autophagic degradation of ubiquitinated proteins. TP53INP2 ablation mitigates experimental diabetes-associated muscle loss, and its overexpression/absence does not affect denervation-induced wasting (where autophagy is blocked), placing TP53INP2 specifically upstream of autophagy-dependent muscle mass regulation.\",\n      \"method\": \"Transgenic mouse models (muscle-specific overexpression and knockout), streptozotocin-induced diabetes model, denervation model, autophagy flux assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo genetic models with defined phenotypic readouts and epistasis via denervation control, replicated across conditions\",\n      \"pmids\": [\"24713655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TP53INP2 localizes to the nucleolus via a C-terminal nucleolar localization signal (NoLS). ChIP assays detect TP53INP2 association with ribosomal DNA (rDNA). Exclusion of TP53INP2 from the nucleolus represses rDNA promoter activity and reduces rRNA and ribosomal protein production. TP53INP2 directly interacts with and is required for assembly of the POLR1/RNA polymerase I preinitiation complex (PIC) at rDNA promoters, revealing a role in promoting ribosome biogenesis.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), nucleolar localization assays, RNA polymerase I PIC interaction and assembly assays, rRNA production measurements\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, direct interaction assays, and functional promoter activity readouts in one study with multiple orthogonal methods\",\n      \"pmids\": [\"27172002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TP53INP2 negatively regulates adipogenesis in preadipocytes by promoting autophagy-dependent sequestration of GSK3β into late endosomes in an ESCRT-dependent manner. This sequestration increases β-catenin levels and enhances TCF/LEF transcriptional activity. TP53INP2 ablation in mice causes enhanced adiposity with greater cellularity of subcutaneous adipose tissue and increased expression of adipogenic master genes.\",\n      \"method\": \"Transgenic mouse models (TP53INP2 knockout), preadipocyte differentiation assays, late endosome fractionation, β-catenin/TCF-LEF reporter assays, ESCRT inhibition experiments\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout phenotype, mechanistic pathway dissection via endosomal fractionation and reporter assays, ESCRT dependency established\",\n      \"pmids\": [\"29593329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TP53INP2 sensitizes cells to death receptor-induced apoptosis by binding both caspase-8 and the ubiquitin ligase TRAF6, functioning as a scaffold that bridges ubiquitinated caspase-8 to TRAF6 for further polyubiquitination and activation of caspase-8. A TRAF6-interacting motif (TIM) and a ubiquitin-interacting motif (UIM) in TP53INP2 are required; mutations of key TIM residues abrogate TRAF6 and caspase-8 interaction and reduce death receptor-induced apoptosis. TP53INP2 deficiency in cultured cells or mouse livers protects against death receptor-induced apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis of TIM and UIM motifs, in vivo mouse liver apoptosis model, apoptosis assays with TRAIL/FasL\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, mutagenesis of defined motifs, in vivo liver model, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"30979779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cytoplasmic TP53INP2 promotes autophagosome biogenesis by directly interacting with ATG7 to form a LC3B-TP53INP2-ATG7 ternary complex. The N-terminal region of TP53INP2 (including the LIR) is sufficient to trigger LC3B-PE lipidation and autophagosome formation. Loss of TP53INP2-LC3 or TP53INP2-ATG7 interaction significantly reduces LC3B-ATG7 binding. TP53INP2 colocalizes with early autophagic membrane structures (ATG14, DFCP1, WIPI2-positive).\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, LIR mutant analysis (W35A/I38A), autophagosome formation assays, fluorescence colocalization, LC3B-PE lipidation assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, mutagenesis, lipidation assay, colocalization, multiple orthogonal methods confirming direct TP53INP2-ATG7 interaction and functional consequence\",\n      \"pmids\": [\"30767704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TP53INP2 contains a ubiquitin-interacting motif (UIM) that mediates binding to ubiquitin and ubiquitinated proteins. TP53INP2 lacking the UIM can displace the autophagic adaptor p62 from LC3, leading to accumulation of ubiquitinated proteins; overexpression of UIM-deficient TP53INP2 sensitizes cells to chloroquine. This indicates TP53INP2 can act as a novel autophagic adaptor recruiting ubiquitinated substrates to autophagosomes.\",\n      \"method\": \"UIM domain deletion mutagenesis, ubiquitin binding assays, co-immunoprecipitation, autophagy flux assays, chloroquine sensitivity assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — mutagenesis and pulldown in a single lab study, functional consequences shown but single paper\",\n      \"pmids\": [\"31155706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"hnRNP A2 controls alternative splicing of an exon in the 5' UTR of TP53INP2 in a 3D matrix-dependent fashion; this splicing event is required for invasive cell migration into extracellular matrix, with consequences mediated via alterations in Golgi complex integrity during 3D migration.\",\n      \"method\": \"siRNA knockdown of hnRNP A2, exon-tiling microarrays, 3D matrix invasion assays, Golgi morphology analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — exon-tiling arrays plus functional invasion assay and Golgi readout, single lab but two orthogonal approaches\",\n      \"pmids\": [\"19934309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FTO-mediated m6A demethylation upregulates TP53INP2 expression in NPM1-mutated AML cells. Mutant NPM1 directly interacts with TP53INP2 and delocalizes it to the cytoplasm. Cytoplasmic TP53INP2 then enhances autophagy by promoting LC3-ATG7 interaction, facilitating leukemia cell survival.\",\n      \"method\": \"Co-immunoprecipitation (TP53INP2 with mutant NPM1), m6A modification assays (FTO), LC3-ATG7 interaction assays, gain/loss-of-function in AML cells\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and functional assays in a single lab, mechanistic linkage across FTO→TP53INP2→LC3/ATG7 supported by multiple experiments\",\n      \"pmids\": [\"36675134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TP53INP2 is predominantly degraded by nuclear proteasomes under basal conditions. Under starvation or chemical stress, TP53INP2 accumulates in the cytoplasm independently of ATG5, CRM1-mediated export, phosphorylation, ubiquitylation, or acetylation. A C-terminal nuclear localization signal (NLS) overlapping a nucleolar localization signal (NoLS) mediates nuclear import and nucleolar enrichment; a conserved nine-amino-acid cytoplasmic retention motif (CRM) in the C-terminus prevents nuclear re-entry under stress. FRAP and importin-binding assays show starvation disrupts nuclear import. Starvation also enhances TP53INP2 translation via FTO-mediated m6A demethylation without altering mRNA stability.\",\n      \"method\": \"CRISPR/Cas9 knockout + EGFP-TP53INP2 reconstitution, deletion mutagenesis, FRAP, importin-binding assays, proteasome inhibitor experiments, ATG5 KO epistasis, m6A/FTO assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — FRAP, importin binding, CRISPR reconstitution, mutagenesis of NLS/NoLS/CRM, and epistasis all in one study with multiple rigorous orthogonal methods\",\n      \"pmids\": [\"41368677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The TP53INP2 LIR motif binds preferentially to GABARAP subfamily proteins over LC3 subfamily proteins. Crystal structures of TP53INP2LIR complexes with GABARAP and LC3A (acetylated and deacetylated) reveal a β-sheet interaction in TP53INP2LIR that determines GABARAP selectivity. Acetylation of the second conserved Lys residue (K49 in LC3B equivalent) in GABARAP or LC3A disrupts interaction with TP53INP2 and impairs nuclear/cytoplasmic LC3 shuttling in cells.\",\n      \"method\": \"Isothermal titration calorimetry (ITC), X-ray crystallography (crystal structures of TP53INP2LIR-GABARAP and TP53INP2LIR-LC3A complexes), acetyl-mimetic mutant cell assays, colocalization studies\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures plus ITC biophysics plus cell-based validation with mutagenesis, multiple orthogonal methods in one study\",\n      \"pmids\": [\"38726830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TP53INP2 localizes predominantly to mitochondria in dedifferentiated liposarcoma cells and promotes mitophagic degradation of YAP in a VDAC1-dependent manner. The WW domain of YAP and the PPTY motif of VDAC1 are required for YAP-VDAC1 interaction. TP53INP2 gain/loss-of-function experiments show it inhibits proliferation, migration, stemness, and dedifferentiation of DDLPS cells.\",\n      \"method\": \"Subcellular fractionation/mitochondrial localization, gain/loss-of-function in DDLPS cell lines, domain mutant analysis (WW domain, PPTY motif), mitophagy assays, YAP protein level/activity measurements\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — mitochondrial localization shown, domain mutagenesis, and functional phenotype, but single lab, single paper\",\n      \"pmids\": [\"40185868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In mature adipocytes, TP53INP2 acts as an adaptor protein for lipophagy by directly binding to lipid droplet-associated protein perilipin 1 (PLIN1) and to LC3 via its LIR motif. Co-IP confirmed TP53INP2-PLIN1 interaction. TP53INP2 knockdown impairs lipophagy and prevents PLIN1 degradation, even though general autophagy (p62-LC3) continues, indicating selective lipophagy adaptor function.\",\n      \"method\": \"Co-immunoprecipitation (TP53INP2-PLIN1, TP53INP2-LC3), siRNA knockdown, lipophagy flux assays in 3T3L1 cells, starvation induction\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and siRNA KD in a single lab, single paper; novel finding but limited orthogonal validation\",\n      \"pmids\": [\"40484366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Oxidative stress-induced downregulation of TP53INP2 in BMSCs is mediated by the autophagy-lysosome degradation pathway, as autophagy inhibition with bafilomycin A1 rescues TP53INP2 protein levels. TP53INP2 knockdown inhibits osteogenic differentiation of BMSCs while overexpression promotes it, acting through activation of Wnt/β-catenin signaling (DKK1 abrogated and lithium rescued these effects).\",\n      \"method\": \"siRNA knockdown, overexpression, bafilomycin A1 treatment, Wnt/β-catenin pathway assays, osteogenic differentiation assays in BMSCs and OVX mouse model\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function with pathway rescue using DKK1 and lithium, in vitro and in vivo, single lab\",\n      \"pmids\": [\"33636337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZSCAN18 functions as a transcription factor that binds the TP53INP2 promoter and transcriptionally activates TP53INP2 expression in gastric cancer cells. Knockdown of TP53INP2 alleviates the tumor-suppressive effects of ZSCAN18 overexpression, placing TP53INP2 downstream of ZSCAN18 in an autophagy-promoting tumor-suppressive axis.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for ZSCAN18 at TP53INP2 promoter, epistasis by TP53INP2 siRNA knockdown in ZSCAN18-overexpressing cells, in vitro and in vivo tumor assays\",\n      \"journal\": \"Clinical epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus genetic epistasis, single lab with two orthogonal methods\",\n      \"pmids\": [\"36650573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cytoplasmic TP53INP2 (maintained by mutant NPM1) functions as a scaffold bridging TRAF6 to caspase-8, promoting caspase-8 ubiquitination and activation via the extrinsic apoptosis pathway in AML cells with NPM1 mutations. This was confirmed by co-immunoprecipitation and ubiquitination assays in gain/loss-of-function experiments.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, gain/loss-of-function experiments, CDX and PDX mouse models, flow cytometry for apoptosis\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo PDX model, single lab, consistent with prior EMBO Journal data\",\n      \"pmids\": [\"38909249\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TP53INP2/DOR is a multifunctional scaffold protein that acts as a sensor of nutrient status: under basal conditions it resides in the nucleus (where it is degraded by nuclear proteasomes) and nucleolus (where it promotes rDNA transcription by facilitating RNA Pol I preinitiation complex assembly), but upon starvation or stress it accumulates in the cytoplasm via a conserved cytoplasmic retention motif (CRM) and disrupted importin-mediated nuclear import; in the cytoplasm it promotes autophagosome biogenesis by binding deacetylated Atg8-family proteins (preferentially GABARAP subfamily) through its LIR motif and by scaffolding an LC3B–TP53INP2–ATG7 complex that promotes LC3 lipidation, while its ubiquitin-interacting motif (UIM) enables recruitment of ubiquitinated cargo to autophagosomes; independently, TP53INP2 sensitizes cells to death receptor-induced apoptosis by bridging TRAF6 to caspase-8 for polyubiquitination and activation; it also regulates adipogenesis and muscle mass through autophagy-dependent sequestration of GSK3β into late endosomes (activating β-catenin) and promotes lipophagy in mature adipocytes by binding perilipin 1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TP53INP2 (DOR) is a nutrient-responsive scaffold protein that couples subcellular localization to dual roles in ribosome biogenesis and autophagy [#0, #3, #10]. Under basal conditions it is imported into the nucleus and nucleolus via a C-terminal NLS/NoLS, where nuclear proteasomes degrade most of the pool and where it associates with rDNA and is required for assembly of the RNA polymerase I preinitiation complex, thereby promoting rRNA synthesis and ribosome biogenesis [#3, #10]. Upon starvation or stress, disrupted importin-mediated import together with a conserved C-terminal cytoplasmic retention motif drives cytoplasmic accumulation, an event independent of CRM1 export, ubiquitylation, or acetylation and reinforced by FTO-mediated m6A demethylation that enhances its translation [#10]. In the cytoplasm TP53INP2 functions as a positive regulator of autophagosome biogenesis: it binds Atg8-family proteins through a LIR motif with structural preference for the GABARAP subfamily, an interaction abrogated by acetylation of a conserved Atg8 lysine, and it directly engages ATG7 to form an LC3B–TP53INP2–ATG7 ternary complex that promotes LC3 lipidation and autophagosome formation [#0, #6, #11]. Its ubiquitin-interacting motif allows recruitment of ubiquitinated cargo, enabling p62-independent autophagic degradation, a function confirmed in skeletal muscle where TP53INP2 controls muscle mass through autophagy-dependent protein degradation [#2, #7]. As a selective adaptor it also mediates lipophagy by bridging perilipin 1 to LC3 in adipocytes and regulates adipogenesis by promoting autophagy- and ESCRT-dependent sequestration of GSK3β into late endosomes to activate β-catenin/TCF-LEF signaling [#4, #13]. Independently of autophagy, TP53INP2 sensitizes cells to death receptor–induced apoptosis by acting as a scaffold that bridges ubiquitinated caspase-8 to the ligase TRAF6 via dedicated TRAF6-interacting (TIM) and ubiquitin-interacting (UIM) motifs, promoting caspase-8 polyubiquitination and activation [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established TP53INP2 as a required factor for autophagy that physically links the Atg8 conjugation machinery to autophagosome membranes, defining its core cellular role.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, BRET, siRNA knockdown with autophagosome quantification, and microscopy in mammalian cells\",\n      \"pmids\": [\"19056683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which LIR residues mediate Atg8 binding\", \"Mechanism of nucleus-to-autophagosome relocalization unknown\", \"VMP1-dependence not structurally defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapped the functional architecture, identifying a region containing an NES and a LIR motif and a second conserved region, both required for nuclear exit, transcriptional activity, and autophagy, linking localization control to dual function.\",\n      \"evidence\": \"Phylogenetic reconstruction plus structure/function mutagenesis with transcription, nuclear export, and autophagy readouts\",\n      \"pmids\": [\"22470510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional targets not defined at this stage\", \"Structural basis of LIR-Atg8 selectivity not addressed\", \"Did not distinguish import vs export contributions\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated in vivo that TP53INP2 controls skeletal muscle mass specifically through autophagy-dependent, p62-independent degradation of ubiquitinated proteins, establishing physiological relevance.\",\n      \"evidence\": \"Muscle-specific transgenic overexpression and knockout mice, diabetes and denervation models, autophagy flux assays\",\n      \"pmids\": [\"24713655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo-recognition mechanism for ubiquitinated proteins not yet molecularly defined\", \"Upstream signals controlling muscle TP53INP2 activity unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a nuclear/nucleolar function distinct from autophagy: TP53INP2 promotes ribosome biogenesis by associating with rDNA and enabling RNA Pol I preinitiation complex assembly.\",\n      \"evidence\": \"ChIP at rDNA, nucleolar localization assays, Pol I PIC interaction/assembly assays, rRNA measurements\",\n      \"pmids\": [\"27172002\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct contacts within the Pol I PIC not structurally mapped\", \"How nutrient state toggles between nucleolar and autophagic pools not resolved here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected TP53INP2 to adipogenesis through autophagy- and ESCRT-dependent sequestration of GSK3β into late endosomes, linking it to β-catenin/TCF-LEF transcriptional control.\",\n      \"evidence\": \"Knockout mice, preadipocyte differentiation, late-endosome fractionation, β-catenin/TCF-LEF reporters, ESCRT inhibition\",\n      \"pmids\": [\"29593329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct GSK3β-TP53INP2 binding interface not defined\", \"How ESCRT and autophagy machineries cooperate mechanistically unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined an autophagy-independent apoptotic function: TP53INP2 scaffolds TRAF6 and caspase-8 via TIM and UIM motifs to drive caspase-8 polyubiquitination and death receptor sensitivity.\",\n      \"evidence\": \"Reciprocal Co-IP, TIM/UIM mutagenesis, in vivo mouse liver apoptosis model, TRAIL/FasL assays\",\n      \"pmids\": [\"30979779\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin chain type on caspase-8 not characterized\", \"How apoptotic vs autophagic functions are partitioned not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the autophagosome-biogenesis mechanism by showing TP53INP2 directly binds ATG7 to form an LC3B–TP53INP2–ATG7 ternary complex sufficient to trigger LC3 lipidation.\",\n      \"evidence\": \"Co-IP, GST pulldown, LIR mutant (W35A/I38A), LC3B-PE lipidation assays, colocalization with ATG14/DFCP1/WIPI2\",\n      \"pmids\": [\"30767704\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structure of the ternary complex not determined\", \"Whether ATG7 binding is direct at the same surface as LC3 unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Proposed TP53INP2 as a ubiquitin-binding autophagic adaptor via its UIM, capable of competing with p62 for LC3 and routing ubiquitinated cargo.\",\n      \"evidence\": \"UIM deletion mutagenesis, ubiquitin-binding assays, Co-IP, autophagy flux and chloroquine sensitivity assays\",\n      \"pmids\": [\"31155706\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study without reciprocal in vivo validation\", \"Endogenous ubiquitinated substrates not identified\", \"Relationship to p62 in physiological contexts unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the localization switch: a C-terminal NLS/NoLS drives import and nucleolar enrichment, while a conserved CRM blocks nuclear re-entry under stress, with starvation disrupting importin-mediated import to enforce cytoplasmic accumulation.\",\n      \"evidence\": \"CRISPR knockout/EGFP reconstitution, deletion mutagenesis, FRAP, importin-binding assays, proteasome inhibition, ATG5-KO epistasis, m6A/FTO assays\",\n      \"pmids\": [\"41368677\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The sensor that converts starvation into impaired import not identified\", \"How CRM mechanistically blocks re-entry not structurally defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided the structural and biophysical basis for GABARAP-subfamily selectivity and showed Atg8 acetylation acts as a switch controlling TP53INP2 binding and shuttling.\",\n      \"evidence\": \"ITC, X-ray crystal structures of TP53INP2-LIR with GABARAP and acetylated/deacetylated LC3A, acetyl-mimetic mutant cell assays\",\n      \"pmids\": [\"38726830\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The acetyltransferase/deacetylase regulating Atg8 K49 in this context not identified\", \"Functional consequence of selectivity for specific cargo not dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Multiple tissue- and cancer-context functions (NPM1-mutant AML survival and apoptosis, gastric cancer ZSCAN18 axis, BMSC osteogenesis, DDLPS mitophagy of YAP, adipocyte lipophagy via PLIN1) remain to be integrated into a unified regulatory logic for how TP53INP2's localization and partner choice are selected in each setting.\",\n      \"evidence\": \"Multiple single-lab cancer and differentiation studies\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Context-specific upstream regulators largely uncharacterized\", \"Mitochondrial localization and VDAC1-dependent mitophagy of YAP rest on a single study\", \"Lipophagy adaptor role via PLIN1 not independently confirmed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 6, 13]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [3, 10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 10]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\"LC3B-TP53INP2-ATG7 complex\"],\n    \"partners\": [\"LC3B\", \"GABARAP\", \"GABARAPL2\", \"ATG7\", \"TRAF6\", \"CASP8\", \"PLIN1\", \"VMP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}