id: Q9H9L7 gene_symbol: AKIRIN1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: > AKIRIN1 encodes a conserved nuclear Akirin-family protein that functions as a transcriptional cofactor in inducible gene-expression programs. It also has a context-dependent promyogenic role supporting myoblast and satellite-cell proliferation and differentiation during muscle repair. The protein localizes to the nucleus and nucleoplasm and is not an enzyme; its main role is to help regulate transcription in chromatin-associated nuclear contexts rather than to catalyze a biochemical reaction. alternative_products: - name: '1' id: Q9H9L7-1 - name: '2' id: Q9H9L7-2 sequence_note: VSP_042769 existing_annotations: - term: id: GO:0005634 label: nucleus evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Nuclear localization is the central, conserved cellular context for AKIRIN1. action: ACCEPT reason: The paper that established the human homologs reports strict nuclear localization for HsAkirin1, and the UniProt record also places the protein in the nucleus. This is consistent with the conserved Akirin role as a nuclear transcriptional cofactor. supported_by: - reference_id: PMID:18066067 supporting_text: "strict nuclear localization" - term: id: GO:0045944 label: positive regulation of transcription by RNA polymerase II evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: This captures the best-supported conserved biological process for AKIRIN1. action: ACCEPT reason: AKIRIN1 is best understood as a nuclear cofactor that supports inducible transcriptional output. The canonical Akirin paper places the protein downstream of NF-kappaB-dependent gene expression and describes Akirins as nuclear cofactors regulating transcriptional activities of main transactivators, which fits this GO term well. supported_by: - reference_id: PMID:18066067 supporting_text: "regulating the transcriptional activities of main transactivators" - term: id: GO:0000785 label: chromatin evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Chromatin association is plausible and consistent with the nuclear cofactor role. action: ACCEPT reason: The 2008 paper argues that Akirins likely act by associating with chromatin or the transcriptional engine, and the conserved nuclear localization supports a chromatin-associated transcriptional role. This is not over-specific for the available evidence. supported_by: - reference_id: PMID:18066067 supporting_text: "interacting with components of the chromatin or the transcriptional engine" - term: id: GO:0003712 label: transcription coregulator activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: This is the most direct molecular-function summary for AKIRIN1. action: ACCEPT reason: AKIRIN1 is not a DNA-binding enzyme or a catalytic factor; the direct human and mouse literature supports a nuclear transcriptional cofactor role downstream of NF-kappaB. This MF term is appropriately specific without overstating a direct DNA-binding or catalytic activity. supported_by: - reference_id: PMID:18066067 supporting_text: "novel important nuclear cofactors regulating the transcriptional activities of main transactivators" - term: id: GO:0010592 label: positive regulation of lamellipodium assembly evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: This is a family/orthology-derived motility call that is not supported for human AKIRIN1. action: MARK_AS_OVER_ANNOTATED reason: The conserved human AKIRIN1 literature supports a nuclear transcriptional cofactor role, not direct actin-remodeling or lamellipodium biology. In the same paper, Akirin1 knockout mice were viable and showed no gross developmental abnormalities, which argues against promoting a specific cell-motility process for the human paralog on the basis of family-level transfer alone. supported_by: - reference_id: PMID:18066067 supporting_text: "MmAkirin1-/- mice were born in a Mendelian ratio, grew healthily and did not show gross developmental abnormalities" - reference_id: PMID:18066067 supporting_text: "the functional role of MmAkirin1, attested by its sequence conservation, is unknown thus far" - term: id: GO:0010759 label: positive regulation of macrophage chemotaxis evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: This macrophage-migration term is over-propagated relative to the human AKIRIN1 evidence. action: MARK_AS_OVER_ANNOTATED reason: Human AKIRIN1 is supported as a nuclear transcriptional cofactor, not as a direct regulator of macrophage migration. The family paper specifically notes that the role of Akirin1 is unknown and that the immune-response phenotype belongs to Akirin2, not Akirin1, so this process annotation is too strong for AKIRIN1. supported_by: - reference_id: PMID:18066067 supporting_text: "the functional role of MmAkirin1, attested by its sequence conservation, is unknown thus far" - reference_id: PMID:18066067 supporting_text: "MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6" - term: id: GO:0014839 label: myoblast migration involved in skeletal muscle regeneration evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: This is a real but context-dependent muscle-regeneration annotation, not a core function. action: KEEP_AS_NON_CORE reason: The muscle literature supports AKIRIN1 as a promyogenic factor in satellite-cell activation and regeneration, including increased MyoD/myogenin and improved proliferation/differentiation after AKIRIN1 overexpression. That is sufficient to keep this as a non-core regenerative annotation, but the term is more specific than the evidence and should not be elevated to the main conserved function. supported_by: - reference_id: PMID:23516508 supporting_text: "Akirin1 in myoblasts increased their expression of MyoD and myogenin and improved cellular proliferation and differentiation" - reference_id: file:human/AKIRIN1/AKIRIN1-deep-research-falcon.md supporting_text: "supports myoblast/satellite cell proliferation and differentiation" - term: id: GO:0045663 label: positive regulation of myoblast differentiation evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: This is a supported but non-core promyogenic annotation for human AKIRIN1. action: KEEP_AS_NON_CORE reason: The Falcon deep research and Dong et al. 2013 support AKIRIN1 as a promyogenic nuclear factor. In that study, AKIRIN1 overexpression increased MyoD and myogenin and improved myoblast proliferation and differentiation, so this term is supported. It is still context-specific muscle biology rather than the main conserved function of the protein, so it should be retained as non-core. supported_by: - reference_id: PMID:23516508 supporting_text: "Akirin1 in myoblasts increased their expression of MyoD and myogenin and improved cellular proliferation and differentiation" - reference_id: PMID:23516508 supporting_text: "a promyogenic gene" - reference_id: file:human/AKIRIN1/AKIRIN1-deep-research-falcon.md supporting_text: "promyogenic nuclear factor" - term: id: GO:1902723 label: negative regulation of skeletal muscle satellite cell proliferation evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: This direction is inconsistent with the AKIRIN1 muscle literature. action: MARK_AS_OVER_ANNOTATED reason: >- The direct AKIRIN1 muscle literature supports the opposite direction: AKIRIN1 expression promotes satellite-cell activity, myoblast proliferation, and myogenic differentiation. This negative-regulation term therefore overstates the biology for human AKIRIN1 even though the pathway is clearly linked to muscle repair. supported_by: - reference_id: PMID:23516508 supporting_text: "When myostatin was inhibited in Dex-treated mice, Akirin1 expression increased as did satellite cell activity, muscle regeneration and muscle growth" - reference_id: PMID:23516508 supporting_text: "Akirin1 in myoblasts increased their expression of MyoD and myogenin and improved cellular proliferation and differentiation" - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: This is a redundant but correct UniProt-derived nuclear localization call. action: ACCEPT reason: The subcellular-location mapping agrees with the direct human localization result in PMID:18066067 and does not conflict with the IBA nuclear annotation. supported_by: - reference_id: PMID:18066067 supporting_text: "strict nuclear localization" - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 qualifier: enables review: summary: The interaction evidence is real, but the generic protein-binding parent is too vague. action: MODIFY reason: A direct interaction is supported by the IntAct-derived record, but the annotation should not remain at the uninformative protein-binding parent term. The most conservative informative replacement is protein-containing complex binding. This should not be conflated with the PN projection to proteasome binding, which is not directly supported by the local human literature cache. proposed_replacement_terms: - id: GO:0044877 label: protein-containing complex binding supported_by: - reference_id: file:human/AKIRIN1/AKIRIN1-uniprot.txt supporting_text: "Q9H9L7; Q9HD26: GOPC; NbExp=3; IntAct=EBI-10309796, EBI-349832" - term: id: GO:0010592 label: positive regulation of lamellipodium assembly evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: This family-transfer call is not justified for human AKIRIN1. action: MARK_AS_OVER_ANNOTATED reason: The human paper supports nuclear transcriptional cofactor activity, not a direct lamellipodium-assembly role. This appears to be a propagated family phenotype rather than an AKIRIN1-specific process. supported_by: - reference_id: PMID:18066067 supporting_text: "regulating the transcriptional activities of main transactivators" - term: id: GO:0010759 label: positive regulation of macrophage chemotaxis evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: This is an over-specific immune-cell migration annotation for human AKIRIN1. action: MARK_AS_OVER_ANNOTATED reason: The direct evidence does not support macrophage chemotaxis as an AKIRIN1 function. The family-level literature instead separates the immune-response phenotype onto Akirin2. supported_by: - reference_id: PMID:18066067 supporting_text: "MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6" - term: id: GO:0014839 label: myoblast migration involved in skeletal muscle regeneration evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: This is a real but context-dependent muscle-regeneration annotation, not a core function. action: KEEP_AS_NON_CORE reason: >- The deeper muscle literature supports AKIRIN1 in myoblast/satellite-cell proliferation and differentiation during regeneration. That is sufficient to keep the lineage-specific regeneration call as non-core, but not as a primary conserved function for AKIRIN1. supported_by: - reference_id: PMID:23516508 supporting_text: "Akirin1 in myoblasts increased their expression of MyoD and myogenin and improved cellular proliferation and differentiation" - reference_id: file:human/AKIRIN1/AKIRIN1-deep-research-falcon.md supporting_text: "supports myoblast/satellite cell proliferation and differentiation" - term: id: GO:0045663 label: positive regulation of myoblast differentiation evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: This is a supported but non-core promyogenic annotation for human AKIRIN1. action: KEEP_AS_NON_CORE reason: >- Dong et al. 2013 directly links AKIRIN1 to promyogenic behavior: in myoblasts, AKIRIN1 overexpression increased MyoD and myogenin and improved proliferation and differentiation. This supports the annotation, but it remains a context-dependent muscle-repair function rather than the principal conserved role of the protein. supported_by: - reference_id: PMID:23516508 supporting_text: "Akirin1 in myoblasts increased their expression of MyoD and myogenin and improved cellular proliferation and differentiation" - reference_id: PMID:23516508 supporting_text: "a promyogenic gene" - reference_id: file:human/AKIRIN1/AKIRIN1-deep-research-falcon.md supporting_text: "promyogenic nuclear factor" - term: id: GO:0045944 label: positive regulation of transcription by RNA polymerase II evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: This is the same core transcriptional role seen in the experimentally supported set. action: ACCEPT reason: The IEA ortholog transfer is consistent with the direct human evidence that Akirins regulate transcriptional output downstream of NF-kappaB. supported_by: - reference_id: PMID:18066067 supporting_text: "regulating the transcriptional activities of main transactivators" - term: id: GO:1902723 label: negative regulation of skeletal muscle satellite cell proliferation evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: This direction is inconsistent with the AKIRIN1 muscle literature. action: MARK_AS_OVER_ANNOTATED reason: >- The available muscle literature supports AKIRIN1 as a positive regulator of satellite-cell activity and regeneration, not as a negative regulator. This term therefore conflicts with the promyogenic evidence and should not be kept. supported_by: - reference_id: PMID:23516508 supporting_text: "When myostatin was inhibited in Dex-treated mice, Akirin1 expression increased as did satellite cell activity, muscle regeneration and muscle growth" - reference_id: PMID:23516508 supporting_text: "Akirin1 in myoblasts increased their expression of MyoD and myogenin and improved cellular proliferation and differentiation" - term: id: GO:1902725 label: negative regulation of satellite cell differentiation evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: This direction is inconsistent with the AKIRIN1 muscle literature. action: MARK_AS_OVER_ANNOTATED reason: >- The muscle paper shows the opposite direction: AKIRIN1 increases myogenic regulators and improves differentiation. That makes this negative-regulation term a poor fit for AKIRIN1 even though the pathway is relevant to muscle repair. supported_by: - reference_id: PMID:23516508 supporting_text: "Akirin1 in myoblasts increased their expression of MyoD and myogenin and improved cellular proliferation and differentiation" - reference_id: PMID:23516508 supporting_text: "a promyogenic gene" - term: id: GO:0005654 label: nucleoplasm evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Direct experimental localization to the nucleoplasm is compatible with the nuclear role. action: ACCEPT reason: This narrower nuclear compartment annotation is compatible with the direct nuclear localization evidence and does not conflict with the IBA nucleus term. It is reasonable to retain as a finer-grained CC call. supported_by: - reference_id: PMID:18066067 supporting_text: "strict nuclear localization" - term: id: GO:0045663 label: positive regulation of myoblast differentiation evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: The ISS transfer duplicates an over-specific muscle process call. action: KEEP_AS_NON_CORE reason: > The same logic applied to the IBA/IEA versions applies here: the direct AKIRIN1 evidence is nuclear transcriptional cofactor activity, but the muscle paper still supports a context-dependent promyogenic role. Keep this as non-core rather than over-annotation. supported_by: - reference_id: PMID:23516508 supporting_text: "Akirin1 in myoblasts increased their expression of MyoD and myogenin and improved cellular proliferation and differentiation" - term: id: GO:0045944 label: positive regulation of transcription by RNA polymerase II evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: This ISS transfer is consistent with the conserved transcriptional core function. action: ACCEPT reason: The orthology-based transfer is reasonable because the direct literature supports the same transcriptional role in human AKIRIN1. supported_by: - reference_id: PMID:18066067 supporting_text: "regulating the transcriptional activities of main transactivators" - term: id: GO:0010592 label: positive regulation of lamellipodium assembly evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: This ISS lamellipodium call is an over-annotation. action: MARK_AS_OVER_ANNOTATED reason: The direct AKIRIN1 literature does not support lamellipodium assembly as a core function of the human protein; retain the nuclear transcriptional role instead. supported_by: - reference_id: PMID:18066067 supporting_text: "strict nuclear localization" - term: id: GO:0010759 label: positive regulation of macrophage chemotaxis evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: This ISS macrophage-chemotaxis call is over-specific for human AKIRIN1. action: MARK_AS_OVER_ANNOTATED reason: The direct literature does not support this immune-cell migration process for AKIRIN1; the immune-response phenotype in the family is better attributed to Akirin2. supported_by: - reference_id: PMID:18066067 supporting_text: "MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6" - term: id: GO:0014839 label: myoblast migration involved in skeletal muscle regeneration evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: This ISS muscle-regeneration call is an over-annotation for the human paralog. action: KEEP_AS_NON_CORE reason: AKIRIN1 is supported as a nuclear transcriptional cofactor, but the muscle literature still supports a context-dependent promyogenic role. Keep this as non-core rather than removing it entirely. supported_by: - reference_id: PMID:23516508 supporting_text: "Akirin1 in myoblasts increased their expression of MyoD and myogenin and improved cellular proliferation and differentiation" - term: id: GO:1902723 label: negative regulation of skeletal muscle satellite cell proliferation evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: This ISS satellite-cell proliferation term is too specific for AKIRIN1. action: MARK_AS_OVER_ANNOTATED reason: No direct AKIRIN1 evidence supports this phenotype-like process term. supported_by: - reference_id: PMID:18066067 supporting_text: "the functional role of MmAkirin1, attested by its sequence conservation, is unknown thus far" - term: id: GO:1902725 label: negative regulation of satellite cell differentiation evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: This ISS satellite-cell differentiation call is also over-annotated. action: MARK_AS_OVER_ANNOTATED reason: The available evidence supports a transcriptional cofactor role rather than a satellite-cell differentiation function. supported_by: - reference_id: PMID:18066067 supporting_text: "novel important nuclear cofactors regulating the transcriptional activities of main transactivators" - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:18066067 qualifier: located_in review: summary: Direct experimental localization to the nucleus is well supported. action: ACCEPT reason: This is the key experimental localization result for human Akirin1 and is perfectly consistent with the conserved nuclear cofactor model. supported_by: - reference_id: PMID:18066067 supporting_text: "strict nuclear localization" references: - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: PMID:18066067 title: Akirins are highly conserved nuclear proteins required for NF-kappaB-dependent gene expression in drosophila and mice. findings: - statement: Human AKIRIN1 localizes to the nucleus and Akirins function as conserved nuclear cofactors in NF-kappaB-dependent gene expression. - id: PMID:23516508 title: Myostatin suppression of Akirin1 mediates glucocorticoid-induced satellite cell dysfunction. findings: - statement: AKIRIN1 has a context-dependent promyogenic role in myoblast and satellite-cell proliferation and differentiation during muscle repair. - id: PMID:34711951 title: AKIRIN2 controls the nuclear import of proteasomes in vertebrates. findings: - statement: This paper supports AKIRIN2-centered proteasome import and does not provide positive evidence for AKIRIN1 as a proteasome importer; it is best treated as a negative contrast for the AKIRIN1 proteostasis projection. - id: PMID:25416956 title: A proteome-scale map of the human interactome network. findings: - statement: This is a high-throughput human PPI map; it supports interaction evidence but not a proteasome-specific AKIRIN1 function. core_functions: - description: Conserved nuclear transcriptional cofactor that helps drive inducible gene-expression programs, especially NF-kappaB-dependent transcription. molecular_function: id: GO:0003712 label: transcription coregulator activity directly_involved_in: - id: GO:0045944 label: positive regulation of transcription by RNA polymerase II supported_by: - reference_id: PMID:18066067 supporting_text: "regulating the transcriptional activities of main transactivators" - reference_id: PMID:18066067 supporting_text: "together with or downstream of NF-κB" - reference_id: file:human/AKIRIN1/AKIRIN1-deep-research-falcon.md supporting_text: "promyogenic nuclear factor" - reference_id: file:human/AKIRIN1/AKIRIN1-deep-research-falcon.md supporting_text: "supports myoblast/satellite cell proliferation and differentiation" - description: Context-dependent promyogenic nuclear regulator that supports myoblast and satellite-cell proliferation and differentiation during muscle repair. molecular_function: id: GO:0003712 label: transcription coregulator activity supported_by: - reference_id: PMID:23516508 supporting_text: "a promyogenic gene" - reference_id: PMID:23516508 supporting_text: "Akirin1 in myoblasts increased their expression of MyoD and myogenin and improved cellular proliferation and differentiation" - reference_id: file:human/AKIRIN1/AKIRIN1-deep-research-falcon.md supporting_text: "promyogenic nuclear factor" - reference_id: file:human/AKIRIN1/AKIRIN1-deep-research-falcon.md supporting_text: "supports myoblast/satellite cell proliferation and differentiation" proposed_new_terms: [] suggested_questions: - question: Is there any direct human evidence that AKIRIN1 binds the proteasome or a proteasome-adaptor complex, given that PMID:34711951 supports AKIRIN2 proteasome import and UniProt explicitly contrasts AKIRIN1 with that activity? - question: Do the muscle and motility annotations belong to AKIRIN1 specifically, or are they better treated as family/paralog transfer that should remain out of the human review? suggested_experiments: - description: Test AKIRIN1 proximity to proteasome subunits and adaptor/shuttle proteins in human cells by co-IP or proximity labeling under basal and stimulated conditions. - description: Deplete or edit AKIRIN1 in a human cell model and measure NF-kappaB-dependent transcription plus chromatin association at inducible target loci.