{"gene":"AKIRIN2","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2021,"finding":"AKIRIN2 forms homodimers that directly bind to fully assembled 20S proteasomes and mediates their nuclear import in vertebrates. During mitosis, proteasomes are excluded from condensing chromatin and re-imported into daughter nuclei in an AKIRIN2-dependent process; cells lacking AKIRIN2 become devoid of nuclear proteasomes, causing accumulation of MYC and other nuclear proteins.","method":"CRISPR screen, Co-IP, intracellular immunostaining, FACS, live imaging, loss-of-function experiments with defined molecular phenotype","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (CRISPR screen, direct binding assays, live imaging, functional rescue) in a single rigorous study, replicated by preprint","pmids":["34711951"],"is_preprint":false},{"year":2024,"finding":"AKIRIN2 acts as a multivalent scaffold protein for proteasome nuclear import: a wing helix in its disordered region stabilizes proteasome interactions; AKIRIN2 homodimers recruit importin IPO9, which facilitates binding of a second AKIRIN2 homodimer that recruits additional importins, amplifying nuclear localization signals for proteasome translocation. Inside the nucleus, RanGTP dissociates importins and AKIRIN2 is degraded by the proteasome in a ubiquitin-independent manner.","method":"Protein-wide saturation mutagenesis screens, cryo-EM, biochemical reconstitution, FACS- and microscopy-based genetic screens","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure combined with reconstitution, mutagenesis, and functional screens in a single study","pmids":["bio_10.1101_2024.11.08.622636"],"is_preprint":true},{"year":2014,"finding":"AKIRIN2 bridges NF-κB and the SWI/SNF chromatin remodeling complex by interacting with BAF60 proteins and IκB-ζ (which forms a complex with NF-κB p50). This IκB-ζ–AKIRIN2–BAF60 complex is essential for TLR-, RIG-I-, and Listeria-mediated expression of proinflammatory genes (Il6, Il12b) in macrophages. Recruitment of AKIRIN2 and IκB-ζ to the Il6 promoter is mutually dependent.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, macrophage-specific knockout, gene expression analysis, infection model","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ChIP, conditional KO with defined transcriptional phenotype, replicated across multiple stimuli","pmids":["25107474"],"is_preprint":false},{"year":2015,"finding":"AKIRIN2 is required for B cell cycle progression and humoral immune responses by controlling SWI/SNF complex recruitment (BRG1/Brg1) to the Myc and Ccnd2 promoters; B cell-specific Akirin2 knockout impairs cyclin D and c-Myc expression and causes proliferation defects and increased apoptosis.","method":"B cell-specific conditional knockout (Cd19-Cre), chromatin immunoprecipitation at Myc and Ccnd2 promoters, cell cycle analysis, in vivo immunization assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with specific molecular phenotype (ChIP-confirmed Brg1 loss at target promoters) and in vivo immune response readout","pmids":["26041538"],"is_preprint":false},{"year":2016,"finding":"AKIRIN2 is required for embryonic formation of the cerebral cortex; cortex-restricted Akirin2 knockout causes massive apoptosis of early cortical progenitors, failed proliferation, reduced neuron production, and disrupted Wnt3a/cortical hem signaling. Sox2-positive progenitors spill into the lateral ventricle, indicating disrupted apical ventricular surface integrity.","method":"Emx1-Cre conditional knockout, immunohistochemistry, EdU labeling, in situ hybridization, cell cycle analysis","journal":"Neural development","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with multiple cellular and molecular phenotypic readouts including pathway marker analysis","pmids":["27871306"],"is_preprint":false},{"year":2017,"finding":"AKIRIN2 is required for neural development in Xenopus: knockdown expands Sox2 (neural progenitor) expression and inhibits N-tubulin (differentiated neuron) expression. AKIRIN2 acts antagonistically to Geminin to regulate Sox2 expression, maintains neural precursor state via BAF53a-containing BAF/SWI/SNF complex, and modulates N-tubulin expression upstream of NeuroD and in parallel with Ngnr1.","method":"Morpholino knockdown in Xenopus, in situ hybridization, co-immunoprecipitation with BAF53a, epistasis experiments with Geminin/NeuroD/Ngnr1","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis and Co-IP in Xenopus ortholog, single lab","pmids":["28193841"],"is_preprint":false},{"year":2019,"finding":"AKIRIN2 is required in vivo for mammalian muscle formation: loss of Akirin2 in somitic muscle precursors causes complete absence of forelimb, intercostal, and diaphragm muscles due to apoptosis of Pax3-positive myoblasts, and impairs expression of myogenin and myosin heavy chain differentiation factors.","method":"Sim1-Cre conditional knockout, immunohistochemistry, Western blot for differentiation markers, in vitro myoblast differentiation assay","journal":"Genesis","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with specific molecular phenotype (myogenin, MHC expression loss) and clear in vivo developmental readout","pmids":["30801883"],"is_preprint":false},{"year":2022,"finding":"AKIRIN2 loss in excitatory cortical neurons causes progressive neurodegeneration via necroptosis and upregulation of p53 (Trp53) target genes. Genetic reduction of Trp53 rescues neurodegeneration in Akirin2-null neurons, placing p53 pathways downstream of AKIRIN2 in neuronal maintenance.","method":"Neuron-specific conditional knockout, transcriptome comparison (RNA-seq), genetic epistasis (Trp53 reduction rescue), histological analysis","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 — conditional KO, transcriptomics, and genetic epistasis with rescue experiment establishing pathway position","pmids":["35198879"],"is_preprint":false},{"year":2013,"finding":"The 14-3-3β–FBI1/AKIRIN2 complex acts as a transcriptional repressor by binding to the BCAM promoter and repressing its transcription, as shown by luciferase reporter assay and chromatin immunoprecipitation. AKIRIN2 (FBI1) was identified as a direct binding partner of 14-3-3β.","method":"Co-immunoprecipitation (14-3-3β pulldown of FBI1/AKIRIN2), luciferase reporter assay, chromatin immunoprecipitation at BCAM promoter, antisense knockdown","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ChIP, and reporter assay in single lab study","pmids":["24223164"],"is_preprint":false},{"year":2018,"finding":"AKIRIN2 is required for interdigital tissue regression in the mouse limb; knockout in limb epithelium prevents interdigital cell death, increases cell proliferation, and causes soft-tissue syndactyly associated with perdurance of Fgf8 expression in the interdigital ectoderm, indicating AKIRIN2 is required for downregulation of Fgf8 from the apical ectodermal ridge.","method":"Epithelium-specific conditional knockout, immunohistochemistry, in situ hybridization for Fgf8, cell death/proliferation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with defined molecular phenotype (Fgf8 perdurance), single lab","pmids":["30116001"],"is_preprint":false},{"year":2019,"finding":"AKIRIN2 induces angiogenesis in cholangiocarcinoma by increasing VEGFA expression through activation of the IL-6/STAT3 signaling pathway, and promotes epithelial-mesenchymal transition; miR-490-3p negatively regulates AKIRIN2 expression at the posttranscriptional level by binding to the 3'-UTR of AKIRIN2 mRNA.","method":"Lentiviral overexpression/knockdown, luciferase reporter assay (miR-490-3p binding to AKIRIN2 3'-UTR), in vivo tumor model, western blot for STAT3/VEGFA pathway","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 — mechanistic pathway placement via OE/KD with reporter validation, single lab","pmids":["30886152"],"is_preprint":false},{"year":2024,"finding":"In sea cucumber (Apostichopus japonicus), AjAkirin2 directly interacts with Aj14-3-3ζ protein (confirmed by GST pull-down and co-IP), positively regulates Aj14-3-3ζ expression, and promotes NF-κB signaling (p65, p105) and inflammatory cytokine expression for antibacterial defense.","method":"GST pull-down, co-immunoprecipitation, RNAi knockdown, bacterial challenge survival assay, qPCR","journal":"Fish & shellfish immunology","confidence":"Low","confidence_rationale":"Tier 3 — Co-IP and pulldown in invertebrate model, single lab, limited functional mechanistic follow-up","pmids":["38685443"],"is_preprint":false}],"current_model":"AKIRIN2 is a conserved nuclear scaffold protein with two major mechanistic roles: (1) it forms homodimers that bind fully assembled 20S proteasomes and recruit a multivalent importin cluster (including IPO9) via a wing-helix motif to drive proteasome nuclear import after each cell division, with AKIRIN2 itself subsequently degraded by nuclear proteasomes in a ubiquitin-independent manner; and (2) it bridges transcription factors (NF-κB/IκB-ζ, Twist, p53 pathway) with the BAF/SWI/SNF chromatin remodeling complex through interactions with BAF60 subunits to regulate inflammatory gene expression, B cell proliferation, cortical development, myogenesis, and neuronal maintenance."},"narrative":{"teleology":[{"year":2013,"claim":"Identifying AKIRIN2 as a transcriptional repressor established that it could participate directly in promoter-level gene regulation, not solely signal relay, by showing its complex with 14-3-3β represses BCAM transcription.","evidence":"Co-IP of 14-3-3β–AKIRIN2, ChIP at BCAM promoter, luciferase reporter assay in human cells","pmids":["24223164"],"confidence":"Medium","gaps":["Single target gene (BCAM); genome-wide scope of 14-3-3β–AKIRIN2 repression unknown","Structural basis of 14-3-3β–AKIRIN2 interaction not resolved"]},{"year":2014,"claim":"Defining the IκB-ζ–AKIRIN2–BAF60 bridge established the first molecular mechanism by which AKIRIN2 couples an NF-κB-family factor to SWI/SNF chromatin remodeling at specific inflammatory gene promoters.","evidence":"Reciprocal Co-IP, ChIP at Il6/Il12b promoters, macrophage-specific knockout, multiple innate immune stimuli","pmids":["25107474"],"confidence":"High","gaps":["Which BAF60 paralog is preferred in vivo not fully resolved","Whether AKIRIN2 contacts SWI/SNF subunits beyond BAF60 unknown"]},{"year":2015,"claim":"Showing that AKIRIN2 recruits BRG1/SWI/SNF to Myc and Ccnd2 promoters in B cells extended the bridging mechanism beyond innate immunity to adaptive immunity and cell cycle control.","evidence":"B cell-specific conditional knockout, ChIP for BRG1, cell cycle and immunization assays","pmids":["26041538"],"confidence":"High","gaps":["Whether AKIRIN2 also acts through BAF60 in B cells not directly tested","Transcription factors upstream of AKIRIN2 at Myc/Ccnd2 in B cells not identified"]},{"year":2016,"claim":"Demonstrating that cortex-restricted Akirin2 knockout causes massive progenitor apoptosis and cortical agenesis established AKIRIN2 as essential for cerebral cortex formation and linked it to Wnt3a signaling disruption.","evidence":"Emx1-Cre conditional knockout, EdU labeling, in situ hybridization for Wnt3a and cortical markers","pmids":["27871306"],"confidence":"High","gaps":["Direct molecular target connecting AKIRIN2 to Wnt3a transcription not identified","Whether progenitor apoptosis is proteasome- or transcription-dependent unclear"]},{"year":2017,"claim":"Epistasis experiments in Xenopus positioned AKIRIN2 as an antagonist of Geminin in neural progenitor maintenance, acting through a BAF53a-containing SWI/SNF complex, reinforcing the SWI/SNF-bridging model in neurogenesis.","evidence":"Morpholino knockdown in Xenopus, Co-IP with BAF53a, epistasis with Geminin/NeuroD/Ngnr1","pmids":["28193841"],"confidence":"Medium","gaps":["Morpholino-based; not confirmed by genetic knockout in Xenopus","Direct physical interaction between AKIRIN2 and Geminin not shown"]},{"year":2019,"claim":"Conditional knockout in somitic muscle precursors revealed that AKIRIN2 is indispensable for mammalian skeletal muscle formation by preventing Pax3-positive myoblast apoptosis and enabling myogenin expression, broadening its developmental roles beyond the nervous and immune systems.","evidence":"Sim1-Cre conditional knockout, Western blot for myogenin/MHC, in vitro myoblast differentiation","pmids":["30801883"],"confidence":"High","gaps":["Whether AKIRIN2 acts via SWI/SNF at myogenic promoters not directly tested by ChIP","Relationship between proteasome import function and myogenesis not addressed"]},{"year":2021,"claim":"A CRISPR screen followed by direct binding and imaging studies revealed a fundamentally new function: AKIRIN2 homodimers bind 20S proteasomes and mediate their nuclear import after mitosis, explaining why AKIRIN2 loss depletes nuclear proteasomes and stabilizes substrates like MYC.","evidence":"CRISPR screen, Co-IP, intracellular immunostaining, FACS, live imaging in human cells","pmids":["34711951"],"confidence":"High","gaps":["Structural basis of proteasome binding not yet resolved at atomic level","Relative contribution of proteasome import vs. transcriptional roles to cell viability unknown"]},{"year":2022,"claim":"Genetic epistasis showed that neurodegeneration caused by neuronal AKIRIN2 loss proceeds through p53-dependent necroptosis, positioning p53 downstream of AKIRIN2 in postmitotic neuron survival.","evidence":"Neuron-specific conditional knockout, RNA-seq, genetic rescue by Trp53 reduction","pmids":["35198879"],"confidence":"High","gaps":["Whether p53 accumulation is due to impaired proteasomal degradation or transcriptional de-repression not distinguished","Whether necroptosis mediators (RIPK1/3, MLKL) are directly regulated by AKIRIN2 unknown"]},{"year":2024,"claim":"Cryo-EM and saturation mutagenesis resolved how AKIRIN2 scaffolds proteasome import: a wing-helix motif stabilizes proteasome binding, AKIRIN2 homodimers recruit IPO9, and a second AKIRIN2 dimer amplifies importin recruitment; upon nuclear entry, RanGTP dissociates importins and AKIRIN2 is degraded ubiquitin-independently by the proteasome it delivered.","evidence":"Cryo-EM structure, protein-wide saturation mutagenesis, biochemical reconstitution, FACS-based screens (preprint)","pmids":["bio_10.1101_2024.11.08.622636"],"confidence":"High","gaps":["Preprint; awaits peer review","How AKIRIN2 degradation is triggered specifically inside the nucleus not fully elucidated","Whether other importins beyond IPO9 participate in the complex in vivo not settled"]},{"year":null,"claim":"It remains unknown how AKIRIN2's two major functions — proteasome nuclear import and SWI/SNF-mediated transcriptional regulation — are coordinated, whether they are deployed in the same or distinct cellular contexts, and which function accounts for the apoptotic and proliferative phenotypes observed across tissues.","evidence":"","pmids":[],"confidence":"High","gaps":["No study has separated proteasome-import and transcription-bridging functions using separation-of-function mutants","No structural data for AKIRIN2–BAF60 or AKIRIN2–IκB-ζ interfaces","Relative contribution of each function to disease-relevant phenotypes untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2,3]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,3,8]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,2,3,7]}],"pathway":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2,3,5]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,6,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,5,6,9]}],"complexes":["BAF/SWI/SNF chromatin remodeling complex","20S proteasome import complex"],"partners":["IPO9","NFKBIZ","BAF60","BAF53A","BRG1","YWHAB","TP53"],"other_free_text":[]},"mechanistic_narrative":"AKIRIN2 is a conserved nuclear scaffold protein that operates at the intersection of proteasome homeostasis and chromatin-dependent transcriptional regulation. It forms homodimers that bind fully assembled 20S proteasomes and recruit importin IPO9 through a wing-helix motif, driving nuclear reimport of proteasomes after mitosis; inside the nucleus AKIRIN2 is itself degraded by proteasomes in a ubiquitin-independent manner, and its loss causes nuclear proteasome depletion with consequent accumulation of substrates such as MYC [PMID:34711951]. In a parallel transcriptional role, AKIRIN2 bridges NF-κB/IκB-ζ and other transcription factors to BAF/SWI/SNF chromatin-remodeling complexes via BAF60 subunits, thereby controlling inflammatory gene expression in macrophages, B cell proliferation through Myc and cyclin D2 promoter remodeling, cortical progenitor survival, and myogenic differentiation [PMID:25107474, PMID:26041538, PMID:27871306, PMID:30801883]. Loss of AKIRIN2 in postmitotic cortical neurons triggers p53-dependent necroptotic neurodegeneration, as demonstrated by genetic rescue upon Trp53 reduction [PMID:35198879]."},"prefetch_data":{"uniprot":{"accession":"Q53H80","full_name":"Akirin-2","aliases":[],"length_aa":203,"mass_kda":22.5,"function":"Molecular adapter that acts as a bridge between a variety of multiprotein complexes, and which is involved in embryonic development, immunity, myogenesis and brain development (PubMed:34711951). Plays a key role in nuclear protein degradation by promoting import of proteasomes into the nucleus: directly binds to fully assembled 20S proteasomes at one end and to nuclear import receptor IPO9 at the other end, bridging them together and mediating the import of pre-assembled proteasome complexes through the nuclear pore (PubMed:34711951). Involved in innate immunity by regulating the production of interleukin-6 (IL6) downstream of Toll-like receptor (TLR): acts by bridging the NF-kappa-B inhibitor NFKBIZ and the SWI/SNF complex, leading to promote induction of IL6 (By similarity). Also involved in adaptive immunity by promoting B-cell activation (By similarity). Involved in brain development: required for the survival and proliferation of cerebral cortical progenitor cells (By similarity). Involved in myogenesis: required for skeletal muscle formation and skeletal development, possibly by regulating expression of muscle differentiation factors (By similarity). Also plays a role in facilitating interdigital tissue regression during limb development (By similarity)","subcellular_location":"Nucleus; Cytoplasm; Membrane","url":"https://www.uniprot.org/uniprotkb/Q53H80/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/AKIRIN2","classification":"Common Essential","n_dependent_lines":1152,"n_total_lines":1208,"dependency_fraction":0.9536423841059603},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PSMC4","stoichiometry":0.2},{"gene":"RAN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/AKIRIN2","total_profiled":1310},"omim":[{"mim_id":"615165","title":"AKIRIN 2; AKIRIN2","url":"https://www.omim.org/entry/615165"},{"mim_id":"615164","title":"AKIRIN 1; AKIRIN1","url":"https://www.omim.org/entry/615164"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/AKIRIN2"},"hgnc":{"alias_symbol":["FLJ10342","dJ486L4.2"],"prev_symbol":["C6orf166"]},"alphafold":{"accession":"Q53H80","domains":[{"cath_id":"1.20.5","chopping":"161-194","consensus_level":"medium","plddt":96.3829,"start":161,"end":194}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53H80","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q53H80-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q53H80-F1-predicted_aligned_error_v6.png","plddt_mean":65.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AKIRIN2","jax_strain_url":"https://www.jax.org/strain/search?query=AKIRIN2"},"sequence":{"accession":"Q53H80","fasta_url":"https://rest.uniprot.org/uniprotkb/Q53H80.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q53H80/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53H80"}},"corpus_meta":[{"pmid":"34711951","id":"PMC_34711951","title":"AKIRIN2 controls the nuclear import of proteasomes in vertebrates.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34711951","citation_count":89,"is_preprint":false},{"pmid":"25107474","id":"PMC_25107474","title":"Akirin2 is critical for inducing inflammatory genes by bridging IκB-ζ and the SWI/SNF complex.","date":"2014","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/25107474","citation_count":87,"is_preprint":false},{"pmid":"30886152","id":"PMC_30886152","title":"Akirin2 is modulated by miR-490-3p and facilitates angiogenesis in cholangiocarcinoma through the IL-6/STAT3/VEGFA signaling pathway.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30886152","citation_count":37,"is_preprint":false},{"pmid":"26287257","id":"PMC_26287257","title":"Chromatin Remodeling and Transcriptional Control in Innate Immunity: Emergence of Akirin2 as a Novel 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suicide mission by AKIRIN2 brings intact proteasomes into the nucleus.","date":"2022","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/34995507","citation_count":4,"is_preprint":false},{"pmid":"26782392","id":"PMC_26782392","title":"Akirin2 expression in response to vaccine-induced immunity in chicken.","date":"2015","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/26782392","citation_count":4,"is_preprint":false},{"pmid":"28605346","id":"PMC_28605346","title":"Akirin2-Mediated Transcriptional Control by Recruiting SWI/SNF Complex in B Cells.","date":"2016","source":"Critical reviews in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28605346","citation_count":3,"is_preprint":false},{"pmid":"25098451","id":"PMC_25098451","title":"Cloning and expression pattern of akirin2 gene in broiler.","date":"2014","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25098451","citation_count":3,"is_preprint":false},{"pmid":"38685443","id":"PMC_38685443","title":"Akirin2 enhances antibacterial ability via interacting with 14-3-3ζ in V. splendidus-challenged Apostichopus japonicus.","date":"2024","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38685443","citation_count":3,"is_preprint":false},{"pmid":"32779549","id":"PMC_32779549","title":"Distribution of the variant at AKIRIN2: c.*188G > A in Chinese cattle.","date":"2020","source":"Animal biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/32779549","citation_count":1,"is_preprint":false},{"pmid":"41192674","id":"PMC_41192674","title":"Akirin2 regulates IL-6 expression and contributes to immune defense in silver pomfret (Pampus argenteus).","date":"2025","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41192674","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.08.622636","title":"A multivalent adaptor mechanism drives the nuclear import of proteasomes","date":"2024-11-08","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.08.622636","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17970,"output_tokens":3140,"usd":0.050505},"stage2":{"model":"claude-opus-4-6","input_tokens":6545,"output_tokens":2755,"usd":0.1524},"total_usd":0.202905,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"AKIRIN2 forms homodimers that directly bind to fully assembled 20S proteasomes and mediates their nuclear import in vertebrates. During mitosis, proteasomes are excluded from condensing chromatin and re-imported into daughter nuclei in an AKIRIN2-dependent process; cells lacking AKIRIN2 become devoid of nuclear proteasomes, causing accumulation of MYC and other nuclear proteins.\",\n      \"method\": \"CRISPR screen, Co-IP, intracellular immunostaining, FACS, live imaging, loss-of-function experiments with defined molecular phenotype\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (CRISPR screen, direct binding assays, live imaging, functional rescue) in a single rigorous study, replicated by preprint\",\n      \"pmids\": [\"34711951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AKIRIN2 acts as a multivalent scaffold protein for proteasome nuclear import: a wing helix in its disordered region stabilizes proteasome interactions; AKIRIN2 homodimers recruit importin IPO9, which facilitates binding of a second AKIRIN2 homodimer that recruits additional importins, amplifying nuclear localization signals for proteasome translocation. Inside the nucleus, RanGTP dissociates importins and AKIRIN2 is degraded by the proteasome in a ubiquitin-independent manner.\",\n      \"method\": \"Protein-wide saturation mutagenesis screens, cryo-EM, biochemical reconstitution, FACS- and microscopy-based genetic screens\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure combined with reconstitution, mutagenesis, and functional screens in a single study\",\n      \"pmids\": [\"bio_10.1101_2024.11.08.622636\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AKIRIN2 bridges NF-κB and the SWI/SNF chromatin remodeling complex by interacting with BAF60 proteins and IκB-ζ (which forms a complex with NF-κB p50). This IκB-ζ–AKIRIN2–BAF60 complex is essential for TLR-, RIG-I-, and Listeria-mediated expression of proinflammatory genes (Il6, Il12b) in macrophages. Recruitment of AKIRIN2 and IκB-ζ to the Il6 promoter is mutually dependent.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, macrophage-specific knockout, gene expression analysis, infection model\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP, conditional KO with defined transcriptional phenotype, replicated across multiple stimuli\",\n      \"pmids\": [\"25107474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AKIRIN2 is required for B cell cycle progression and humoral immune responses by controlling SWI/SNF complex recruitment (BRG1/Brg1) to the Myc and Ccnd2 promoters; B cell-specific Akirin2 knockout impairs cyclin D and c-Myc expression and causes proliferation defects and increased apoptosis.\",\n      \"method\": \"B cell-specific conditional knockout (Cd19-Cre), chromatin immunoprecipitation at Myc and Ccnd2 promoters, cell cycle analysis, in vivo immunization assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with specific molecular phenotype (ChIP-confirmed Brg1 loss at target promoters) and in vivo immune response readout\",\n      \"pmids\": [\"26041538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AKIRIN2 is required for embryonic formation of the cerebral cortex; cortex-restricted Akirin2 knockout causes massive apoptosis of early cortical progenitors, failed proliferation, reduced neuron production, and disrupted Wnt3a/cortical hem signaling. Sox2-positive progenitors spill into the lateral ventricle, indicating disrupted apical ventricular surface integrity.\",\n      \"method\": \"Emx1-Cre conditional knockout, immunohistochemistry, EdU labeling, in situ hybridization, cell cycle analysis\",\n      \"journal\": \"Neural development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with multiple cellular and molecular phenotypic readouts including pathway marker analysis\",\n      \"pmids\": [\"27871306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AKIRIN2 is required for neural development in Xenopus: knockdown expands Sox2 (neural progenitor) expression and inhibits N-tubulin (differentiated neuron) expression. AKIRIN2 acts antagonistically to Geminin to regulate Sox2 expression, maintains neural precursor state via BAF53a-containing BAF/SWI/SNF complex, and modulates N-tubulin expression upstream of NeuroD and in parallel with Ngnr1.\",\n      \"method\": \"Morpholino knockdown in Xenopus, in situ hybridization, co-immunoprecipitation with BAF53a, epistasis experiments with Geminin/NeuroD/Ngnr1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis and Co-IP in Xenopus ortholog, single lab\",\n      \"pmids\": [\"28193841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AKIRIN2 is required in vivo for mammalian muscle formation: loss of Akirin2 in somitic muscle precursors causes complete absence of forelimb, intercostal, and diaphragm muscles due to apoptosis of Pax3-positive myoblasts, and impairs expression of myogenin and myosin heavy chain differentiation factors.\",\n      \"method\": \"Sim1-Cre conditional knockout, immunohistochemistry, Western blot for differentiation markers, in vitro myoblast differentiation assay\",\n      \"journal\": \"Genesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with specific molecular phenotype (myogenin, MHC expression loss) and clear in vivo developmental readout\",\n      \"pmids\": [\"30801883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AKIRIN2 loss in excitatory cortical neurons causes progressive neurodegeneration via necroptosis and upregulation of p53 (Trp53) target genes. Genetic reduction of Trp53 rescues neurodegeneration in Akirin2-null neurons, placing p53 pathways downstream of AKIRIN2 in neuronal maintenance.\",\n      \"method\": \"Neuron-specific conditional knockout, transcriptome comparison (RNA-seq), genetic epistasis (Trp53 reduction rescue), histological analysis\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO, transcriptomics, and genetic epistasis with rescue experiment establishing pathway position\",\n      \"pmids\": [\"35198879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The 14-3-3β–FBI1/AKIRIN2 complex acts as a transcriptional repressor by binding to the BCAM promoter and repressing its transcription, as shown by luciferase reporter assay and chromatin immunoprecipitation. AKIRIN2 (FBI1) was identified as a direct binding partner of 14-3-3β.\",\n      \"method\": \"Co-immunoprecipitation (14-3-3β pulldown of FBI1/AKIRIN2), luciferase reporter assay, chromatin immunoprecipitation at BCAM promoter, antisense knockdown\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ChIP, and reporter assay in single lab study\",\n      \"pmids\": [\"24223164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AKIRIN2 is required for interdigital tissue regression in the mouse limb; knockout in limb epithelium prevents interdigital cell death, increases cell proliferation, and causes soft-tissue syndactyly associated with perdurance of Fgf8 expression in the interdigital ectoderm, indicating AKIRIN2 is required for downregulation of Fgf8 from the apical ectodermal ridge.\",\n      \"method\": \"Epithelium-specific conditional knockout, immunohistochemistry, in situ hybridization for Fgf8, cell death/proliferation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined molecular phenotype (Fgf8 perdurance), single lab\",\n      \"pmids\": [\"30116001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AKIRIN2 induces angiogenesis in cholangiocarcinoma by increasing VEGFA expression through activation of the IL-6/STAT3 signaling pathway, and promotes epithelial-mesenchymal transition; miR-490-3p negatively regulates AKIRIN2 expression at the posttranscriptional level by binding to the 3'-UTR of AKIRIN2 mRNA.\",\n      \"method\": \"Lentiviral overexpression/knockdown, luciferase reporter assay (miR-490-3p binding to AKIRIN2 3'-UTR), in vivo tumor model, western blot for STAT3/VEGFA pathway\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic pathway placement via OE/KD with reporter validation, single lab\",\n      \"pmids\": [\"30886152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In sea cucumber (Apostichopus japonicus), AjAkirin2 directly interacts with Aj14-3-3ζ protein (confirmed by GST pull-down and co-IP), positively regulates Aj14-3-3ζ expression, and promotes NF-κB signaling (p65, p105) and inflammatory cytokine expression for antibacterial defense.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, RNAi knockdown, bacterial challenge survival assay, qPCR\",\n      \"journal\": \"Fish & shellfish immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and pulldown in invertebrate model, single lab, limited functional mechanistic follow-up\",\n      \"pmids\": [\"38685443\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AKIRIN2 is a conserved nuclear scaffold protein with two major mechanistic roles: (1) it forms homodimers that bind fully assembled 20S proteasomes and recruit a multivalent importin cluster (including IPO9) via a wing-helix motif to drive proteasome nuclear import after each cell division, with AKIRIN2 itself subsequently degraded by nuclear proteasomes in a ubiquitin-independent manner; and (2) it bridges transcription factors (NF-κB/IκB-ζ, Twist, p53 pathway) with the BAF/SWI/SNF chromatin remodeling complex through interactions with BAF60 subunits to regulate inflammatory gene expression, B cell proliferation, cortical development, myogenesis, and neuronal maintenance.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"AKIRIN2 is a conserved nuclear scaffold protein that operates at the intersection of proteasome homeostasis and chromatin-dependent transcriptional regulation. It forms homodimers that bind fully assembled 20S proteasomes and recruit importin IPO9 through a wing-helix motif, driving nuclear reimport of proteasomes after mitosis; inside the nucleus AKIRIN2 is itself degraded by proteasomes in a ubiquitin-independent manner, and its loss causes nuclear proteasome depletion with consequent accumulation of substrates such as MYC [PMID:34711951]. In a parallel transcriptional role, AKIRIN2 bridges NF-κB/IκB-ζ and other transcription factors to BAF/SWI/SNF chromatin-remodeling complexes via BAF60 subunits, thereby controlling inflammatory gene expression in macrophages, B cell proliferation through Myc and cyclin D2 promoter remodeling, cortical progenitor survival, and myogenic differentiation [PMID:25107474, PMID:26041538, PMID:27871306, PMID:30801883]. Loss of AKIRIN2 in postmitotic cortical neurons triggers p53-dependent necroptotic neurodegeneration, as demonstrated by genetic rescue upon Trp53 reduction [PMID:35198879].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying AKIRIN2 as a transcriptional repressor established that it could participate directly in promoter-level gene regulation, not solely signal relay, by showing its complex with 14-3-3β represses BCAM transcription.\",\n      \"evidence\": \"Co-IP of 14-3-3β–AKIRIN2, ChIP at BCAM promoter, luciferase reporter assay in human cells\",\n      \"pmids\": [\"24223164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single target gene (BCAM); genome-wide scope of 14-3-3β–AKIRIN2 repression unknown\", \"Structural basis of 14-3-3β–AKIRIN2 interaction not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defining the IκB-ζ–AKIRIN2–BAF60 bridge established the first molecular mechanism by which AKIRIN2 couples an NF-κB-family factor to SWI/SNF chromatin remodeling at specific inflammatory gene promoters.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP at Il6/Il12b promoters, macrophage-specific knockout, multiple innate immune stimuli\",\n      \"pmids\": [\"25107474\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which BAF60 paralog is preferred in vivo not fully resolved\", \"Whether AKIRIN2 contacts SWI/SNF subunits beyond BAF60 unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showing that AKIRIN2 recruits BRG1/SWI/SNF to Myc and Ccnd2 promoters in B cells extended the bridging mechanism beyond innate immunity to adaptive immunity and cell cycle control.\",\n      \"evidence\": \"B cell-specific conditional knockout, ChIP for BRG1, cell cycle and immunization assays\",\n      \"pmids\": [\"26041538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AKIRIN2 also acts through BAF60 in B cells not directly tested\", \"Transcription factors upstream of AKIRIN2 at Myc/Ccnd2 in B cells not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating that cortex-restricted Akirin2 knockout causes massive progenitor apoptosis and cortical agenesis established AKIRIN2 as essential for cerebral cortex formation and linked it to Wnt3a signaling disruption.\",\n      \"evidence\": \"Emx1-Cre conditional knockout, EdU labeling, in situ hybridization for Wnt3a and cortical markers\",\n      \"pmids\": [\"27871306\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target connecting AKIRIN2 to Wnt3a transcription not identified\", \"Whether progenitor apoptosis is proteasome- or transcription-dependent unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Epistasis experiments in Xenopus positioned AKIRIN2 as an antagonist of Geminin in neural progenitor maintenance, acting through a BAF53a-containing SWI/SNF complex, reinforcing the SWI/SNF-bridging model in neurogenesis.\",\n      \"evidence\": \"Morpholino knockdown in Xenopus, Co-IP with BAF53a, epistasis with Geminin/NeuroD/Ngnr1\",\n      \"pmids\": [\"28193841\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino-based; not confirmed by genetic knockout in Xenopus\", \"Direct physical interaction between AKIRIN2 and Geminin not shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Conditional knockout in somitic muscle precursors revealed that AKIRIN2 is indispensable for mammalian skeletal muscle formation by preventing Pax3-positive myoblast apoptosis and enabling myogenin expression, broadening its developmental roles beyond the nervous and immune systems.\",\n      \"evidence\": \"Sim1-Cre conditional knockout, Western blot for myogenin/MHC, in vitro myoblast differentiation\",\n      \"pmids\": [\"30801883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AKIRIN2 acts via SWI/SNF at myogenic promoters not directly tested by ChIP\", \"Relationship between proteasome import function and myogenesis not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A CRISPR screen followed by direct binding and imaging studies revealed a fundamentally new function: AKIRIN2 homodimers bind 20S proteasomes and mediate their nuclear import after mitosis, explaining why AKIRIN2 loss depletes nuclear proteasomes and stabilizes substrates like MYC.\",\n      \"evidence\": \"CRISPR screen, Co-IP, intracellular immunostaining, FACS, live imaging in human cells\",\n      \"pmids\": [\"34711951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of proteasome binding not yet resolved at atomic level\", \"Relative contribution of proteasome import vs. transcriptional roles to cell viability unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Genetic epistasis showed that neurodegeneration caused by neuronal AKIRIN2 loss proceeds through p53-dependent necroptosis, positioning p53 downstream of AKIRIN2 in postmitotic neuron survival.\",\n      \"evidence\": \"Neuron-specific conditional knockout, RNA-seq, genetic rescue by Trp53 reduction\",\n      \"pmids\": [\"35198879\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether p53 accumulation is due to impaired proteasomal degradation or transcriptional de-repression not distinguished\", \"Whether necroptosis mediators (RIPK1/3, MLKL) are directly regulated by AKIRIN2 unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cryo-EM and saturation mutagenesis resolved how AKIRIN2 scaffolds proteasome import: a wing-helix motif stabilizes proteasome binding, AKIRIN2 homodimers recruit IPO9, and a second AKIRIN2 dimer amplifies importin recruitment; upon nuclear entry, RanGTP dissociates importins and AKIRIN2 is degraded ubiquitin-independently by the proteasome it delivered.\",\n      \"evidence\": \"Cryo-EM structure, protein-wide saturation mutagenesis, biochemical reconstitution, FACS-based screens (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.11.08.622636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint; awaits peer review\", \"How AKIRIN2 degradation is triggered specifically inside the nucleus not fully elucidated\", \"Whether other importins beyond IPO9 participate in the complex in vivo not settled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how AKIRIN2's two major functions — proteasome nuclear import and SWI/SNF-mediated transcriptional regulation — are coordinated, whether they are deployed in the same or distinct cellular contexts, and which function accounts for the apoptotic and proliferative phenotypes observed across tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No study has separated proteasome-import and transcription-bridging functions using separation-of-function mutants\", \"No structural data for AKIRIN2–BAF60 or AKIRIN2–IκB-ζ interfaces\", \"Relative contribution of each function to disease-relevant phenotypes untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 3, 8]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 2, 3, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2, 3, 5]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 6, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 5, 6, 9]}\n    ],\n    \"complexes\": [\n      \"BAF/SWI/SNF chromatin remodeling complex\",\n      \"20S proteasome import complex\"\n    ],\n    \"partners\": [\n      \"IPO9\",\n      \"NFKBIZ\",\n      \"BAF60\",\n      \"BAF53A\",\n      \"BRG1\",\n      \"YWHAB\",\n      \"TP53\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}