id: Q53H80
gene_symbol: AKIRIN2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: AKIRIN2 encodes a conserved, predominantly nuclear akirin-family adaptor protein. In vertebrate cells, AKIRIN2 homodimers bind assembled proteasomes and the import receptor IPO9 to promote proteasome import into the nucleus, supporting nuclear protein degradation. Akirin proteins also act as nuclear transcriptional coregulators downstream of NF-kappaB and chromatin-remodeling machinery, linking conserved immune and developmental gene-expression programs to a small, domain-poor adaptor protein.
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: AKIRIN2 is well supported as a predominantly nuclear protein by direct human localization data and by the mechanistic proteasome-import study.
    action: ACCEPT
    reason: Nuclear localization is central to both AKIRIN2 proteasome-import and transcription-coregulator biology.
    supported_by:
    - reference_id: PMID:18066067
      supporting_text: Antibody staining of the human cells clearly showed the nuclear localization of HsAkirin1 and HsAkirin2
    - reference_id: PMID:34711951
      supporting_text: nuclear import of proteasomes in vertebrates
- term:
    id: GO:0045089
    label: positive regulation of innate immune response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Akirin2 supports NF-kappaB-dependent innate immune gene expression in model systems, including IL-6 induction downstream of TLR/IL-1R signaling.
    action: KEEP_AS_NON_CORE
    reason: The immune-response annotation is biologically supported but represents a regulatory output context rather than the PN core proteostasis role of AKIRIN2.
    supported_by:
    - reference_id: PMID:18066067
      supporting_text: MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation
    - reference_id: PMID:18066067
      supporting_text: Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
- 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: AKIRIN2 supports NF-kappaB-dependent inducible gene expression and is conserved as a nuclear transcriptional co-regulator.
    action: ACCEPT
    reason: The process term captures a genuine AKIRIN2 transcriptional role, though it is distinct from the PN proteasome-import function.
    supported_by:
    - reference_id: PMID:18066067
      supporting_text: Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
    - reference_id: PMID:18066067
      supporting_text: Akirin is functionally and evolutionary conserved
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: The chromatin IBA annotation is consistent with akirin function as a nuclear transcriptional cofactor associated with chromatin/transcription machinery.
    action: ACCEPT
    reason: AKIRIN2 has a conserved nuclear transcription-coregulator role; chromatin is a reasonable active context for that role.
    additional_reference_ids:
    - PMID:18066067
    supported_by:
    - reference_id: PMID:18066067
      supporting_text: Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
- term:
    id: GO:0003712
    label: transcription coregulator activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Akirin proteins act with or downstream of NF-kappaB and are best interpreted as transcriptional cofactors rather than DNA-binding transcription factors, bridging NF-kappaB output to SWI/SNF chromatin remodelers.
    action: ACCEPT
    reason: This is an appropriate molecular-function annotation for the conserved nuclear gene-expression role; Akirin functions as a coregulator/molecular selector recruiting SWI/SNF rather than binding DNA directly.
    additional_reference_ids:
    - PMID:18066067
    - PMID:25180232
    - PMID:28605346
    supported_by:
    - reference_id: PMID:18066067
      supporting_text: Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: AKIRIN2 is well supported as a predominantly nuclear protein by direct human localization data and by the mechanistic proteasome-import study.
    action: ACCEPT
    reason: Nuclear localization is central to both AKIRIN2 proteasome-import and transcription-coregulator biology.
    supported_by:
    - reference_id: PMID:18066067
      supporting_text: Antibody staining of the human cells clearly showed the nuclear localization of HsAkirin1 and HsAkirin2
    - reference_id: PMID:34711951
      supporting_text: nuclear import of proteasomes in vertebrates
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Cytoplasmic localization is reported by similarity and as a minor compartment in UniProt, but AKIRIN2 is predominantly nuclear.
    action: KEEP_AS_NON_CORE
    reason: Retain as peripheral/subordinate localization rather than a primary active site for the gene product.
    supported_by:
    - reference_id: file:human/AKIRIN2/AKIRIN2-uniprot.txt
      supporting_text: Present mainly in the nuclear fraction, and at much lower level in the cytoplasmic and membrane fractions.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Membrane localization is by similarity and described only as a much lower-level fraction relative to the nucleus.
    action: MARK_AS_OVER_ANNOTATED
    reason: This is likely an over-specific/peripheral localization for human AKIRIN2; the evidence does not support treating membrane as a core cellular context.
    supported_by:
    - reference_id: file:human/AKIRIN2/AKIRIN2-uniprot.txt
      supporting_text: Present mainly in the nuclear fraction, and at much lower level in the cytoplasmic and membrane fractions.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: This PMID:16189514 interaction annotation records a generic high-throughput protein interaction rather than a specific AKIRIN2 activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is not informative for AKIRIN2 curation and should not be used as a core function; mechanistic binding is captured separately as proteasome binding/protein-macromolecule adaptor activity.
    additional_reference_ids:
    - PMID:34711951
    supported_by:
    - reference_id: PMID:34711951
      supporting_text: directly bind to fully assembled 20S proteasomes
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: This PMID:28514442 interaction annotation records a generic high-throughput protein interaction rather than a specific AKIRIN2 activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is not informative for AKIRIN2 curation and should not be used as a core function; mechanistic binding is captured separately as proteasome binding/protein-macromolecule adaptor activity.
    additional_reference_ids:
    - PMID:34711951
    supported_by:
    - reference_id: PMID:34711951
      supporting_text: directly bind to fully assembled 20S proteasomes
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: This PMID:31515488 interaction annotation records a generic high-throughput protein interaction rather than a specific AKIRIN2 activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is not informative for AKIRIN2 curation and should not be used as a core function; mechanistic binding is captured separately as proteasome binding/protein-macromolecule adaptor activity.
    additional_reference_ids:
    - PMID:34711951
    supported_by:
    - reference_id: PMID:34711951
      supporting_text: directly bind to fully assembled 20S proteasomes
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: This PMID:32296183 interaction annotation records a generic high-throughput protein interaction rather than a specific AKIRIN2 activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is not informative for AKIRIN2 curation and should not be used as a core function; mechanistic binding is captured separately as proteasome binding/protein-macromolecule adaptor activity.
    additional_reference_ids:
    - PMID:34711951
    supported_by:
    - reference_id: PMID:34711951
      supporting_text: directly bind to fully assembled 20S proteasomes
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: This PMID:33961781 interaction annotation records a generic high-throughput protein interaction rather than a specific AKIRIN2 activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is not informative for AKIRIN2 curation and should not be used as a core function; mechanistic binding is captured separately as proteasome binding/protein-macromolecule adaptor activity.
    additional_reference_ids:
    - PMID:34711951
    supported_by:
    - reference_id: PMID:34711951
      supporting_text: directly bind to fully assembled 20S proteasomes
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: This PMID:40205054 interaction annotation records a generic high-throughput protein interaction rather than a specific AKIRIN2 activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is not informative for AKIRIN2 curation and should not be used as a core function; mechanistic binding is captured separately as proteasome binding/protein-macromolecule adaptor activity.
    additional_reference_ids:
    - PMID:34711951
    supported_by:
    - reference_id: PMID:34711951
      supporting_text: directly bind to fully assembled 20S proteasomes
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: The binary interactome annotation is generic, but independent mechanistic evidence shows AKIRIN2 forms homodimers.
    action: ACCEPT
    reason: Identical protein binding is supported as a real AKIRIN2 property, although it is secondary to the proteasome-import adaptor role.
    additional_reference_ids:
    - PMID:34711951
    supported_by:
    - reference_id: PMID:34711951
      supporting_text: AKIRIN2 forms homodimers
    - reference_id: file:human/AKIRIN2/AKIRIN2-uniprot.txt
      supporting_text: Homodimer (PubMed:34711951)
- term:
    id: GO:0002821
    label: positive regulation of adaptive immune response
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: positive regulation of adaptive immune response is supported only indirectly/by orthology as an immune-system output of AKIRIN2 transcriptional regulation.
    action: KEEP_AS_NON_CORE
    reason: Keep as a contextual immune/developmental annotation, not as a core AKIRIN2 molecular function or PN proteostasis projection.
    supported_by:
    - reference_id: PMID:18066067
      supporting_text: MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation
    - reference_id: PMID:18066067
      supporting_text: Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
- term:
    id: GO:0009792
    label: embryo development ending in birth or egg hatching
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: embryo development ending in birth or egg hatching is inferred from vertebrate/model-organism developmental phenotypes and is plausible for AKIRIN2 but broad.
    action: KEEP_AS_NON_CORE
    reason: Developmental annotations should be retained as pleiotropic outcome/context terms rather than core PN function assignments.
    additional_reference_ids:
    - PMID:18066067
    supported_by:
    - reference_id: PMID:18066067
      supporting_text: MmAkirin2-/- mice were embryonic lethal
- term:
    id: GO:0021987
    label: cerebral cortex development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: cerebral cortex development is inferred by orthology/by similarity; UniProt specifically describes a role in survival and proliferation of cerebral cortical progenitor cells.
    action: KEEP_AS_NON_CORE
    reason: Retain as a contextual developmental annotation, not as a core PN proteostasis function assignment.
    additional_reference_ids:
    - file:human/AKIRIN2/AKIRIN2-uniprot.txt
    supported_by:
    - reference_id: file:human/AKIRIN2/AKIRIN2-uniprot.txt
      supporting_text: 'Involved in brain development: required for the survival and proliferation of cerebral cortical progenitor cells'
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: AKIRIN2 bridges assembled proteasomes and IPO9 during proteasome nuclear import, matching a protein-macromolecule adaptor role.
    action: ACCEPT
    reason: This is an appropriate core molecular-function annotation and a better functional descriptor than generic protein binding.
    supported_by:
    - reference_id: PMID:34711951
      supporting_text: directly bind to fully assembled 20S proteasomes
    - reference_id: file:human/AKIRIN2/AKIRIN2-uniprot.txt
      supporting_text: directly binds to fully assembled 20S proteasomes at one end and to nuclear import receptor IPO9 at the other end
- term:
    id: GO:0032755
    label: positive regulation of interleukin-6 production
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Mouse Akirin2 loss impairs IL-6 production downstream of TLR/IL-1R stimulation.
    action: KEEP_AS_NON_CORE
    reason: The annotation is valid as an immune transcriptional-output context, but it is not a core PN proteostasis function.
    supported_by:
    - reference_id: PMID:18066067
      supporting_text: MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation
- term:
    id: GO:0042742
    label: defense response to bacterium
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: defense response to bacterium is supported only indirectly/by orthology as an immune-system output of AKIRIN2 transcriptional regulation.
    action: KEEP_AS_NON_CORE
    reason: Keep as a contextual immune/developmental annotation, not as a core AKIRIN2 molecular function or PN proteostasis projection.
    supported_by:
    - reference_id: PMID:18066067
      supporting_text: MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation
    - reference_id: PMID:18066067
      supporting_text: Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
- term:
    id: GO:0045089
    label: positive regulation of innate immune response
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Akirin2 supports NF-kappaB-dependent innate immune gene expression in model systems, including IL-6 induction downstream of TLR/IL-1R signaling.
    action: KEEP_AS_NON_CORE
    reason: The immune-response annotation is biologically supported but represents a regulatory output context rather than the PN core proteostasis role of AKIRIN2.
    supported_by:
    - reference_id: PMID:18066067
      supporting_text: MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation
    - reference_id: PMID:18066067
      supporting_text: Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
- 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: AKIRIN2 supports NF-kappaB-dependent inducible gene expression and is conserved as a nuclear transcriptional co-regulator.
    action: ACCEPT
    reason: The process term captures a genuine AKIRIN2 transcriptional role, though it is distinct from the PN proteasome-import function.
    supported_by:
    - reference_id: PMID:18066067
      supporting_text: Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
    - reference_id: PMID:18066067
      supporting_text: Akirin is functionally and evolutionary conserved
- term:
    id: GO:0050871
    label: positive regulation of B cell activation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: positive regulation of B cell activation is directly supported by a B-cell-specific Akirin2 knockout study showing impaired BRG1 recruitment to Myc/Ccnd2 promoters and defective B-cell proliferation and humoral responses.
    action: KEEP_AS_NON_CORE
    reason: Keep as a contextual immune/developmental annotation, not as a core AKIRIN2 molecular function or PN proteostasis projection; primary experimental support exists but it is a downstream transcriptional output.
    additional_reference_ids:
    - PMID:26041538
    supported_by:
    - reference_id: PMID:18066067
      supporting_text: MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation
    - reference_id: PMID:18066067
      supporting_text: Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
- term:
    id: GO:0051147
    label: regulation of muscle cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: regulation of muscle cell differentiation is inferred by orthology/by similarity; UniProt specifically describes a myogenesis role for AKIRIN2.
    action: KEEP_AS_NON_CORE
    reason: Retain as a contextual developmental annotation, not as a core PN proteostasis function assignment.
    additional_reference_ids:
    - file:human/AKIRIN2/AKIRIN2-uniprot.txt
    supported_by:
    - reference_id: file:human/AKIRIN2/AKIRIN2-uniprot.txt
      supporting_text: 'Involved in myogenesis: required for skeletal muscle formation and skeletal development, possibly by regulating expression of muscle differentiation factors'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: The HPA nucleoplasm annotation is consistent with the direct nuclear localization literature and AKIRIN2 function in nuclear proteasome import.
    action: ACCEPT
    reason: Nucleoplasmic/nuclear localization is compatible with the core nuclear functions of AKIRIN2.
    supported_by:
    - reference_id: PMID:18066067
      supporting_text: Antibody staining of the human cells clearly showed the nuclear localization of HsAkirin1 and HsAkirin2
    - reference_id: PMID:34711951
      supporting_text: nuclear import of proteasomes in vertebrates
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Cytoplasmic localization is reported by similarity and as a minor compartment in UniProt, but AKIRIN2 is predominantly nuclear.
    action: KEEP_AS_NON_CORE
    reason: Retain as peripheral/subordinate localization rather than a primary active site for the gene product.
    supported_by:
    - reference_id: file:human/AKIRIN2/AKIRIN2-uniprot.txt
      supporting_text: Present mainly in the nuclear fraction, and at much lower level in the cytoplasmic and membrane fractions.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Membrane localization is by similarity and described only as a much lower-level fraction relative to the nucleus.
    action: MARK_AS_OVER_ANNOTATED
    reason: This is likely an over-specific/peripheral localization for human AKIRIN2; the evidence does not support treating membrane as a core cellular context.
    supported_by:
    - reference_id: file:human/AKIRIN2/AKIRIN2-uniprot.txt
      supporting_text: Present mainly in the nuclear fraction, and at much lower level in the cytoplasmic and membrane fractions.
- term:
    id: GO:0002821
    label: positive regulation of adaptive immune response
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: positive regulation of adaptive immune response is supported only indirectly/by orthology as an immune-system output of AKIRIN2 transcriptional regulation.
    action: KEEP_AS_NON_CORE
    reason: Keep as a contextual immune/developmental annotation, not as a core AKIRIN2 molecular function or PN proteostasis projection.
    supported_by:
    - reference_id: PMID:18066067
      supporting_text: MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation
    - reference_id: PMID:18066067
      supporting_text: Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34711951
  qualifier: enables
  review:
    summary: The 2021 AKIRIN2 paper supports specific proteasome and IPO9 adaptor interactions, so generic protein binding is too uninformative.
    action: MODIFY
    reason: 'Replace the broad binding annotation with specific, mechanistically supported terms: proteasome binding for the PN projection and protein-macromolecule adaptor activity for the bridging role.'
    proposed_replacement_terms:
    - id: GO:0070628
      label: proteasome binding
    - id: GO:0030674
      label: protein-macromolecule adaptor activity
    additional_reference_ids:
    - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
    supported_by:
    - reference_id: PMID:34711951
      supporting_text: directly bind to fully assembled 20S proteasomes
    - reference_id: file:human/AKIRIN2/AKIRIN2-uniprot.txt
      supporting_text: directly binds to fully assembled 20S proteasomes at one end and to nuclear import receptor IPO9 at the other end
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:34711951
  qualifier: is_active_in
  review:
    summary: AKIRIN2 is well supported as a predominantly nuclear protein by direct human localization data and by the mechanistic proteasome-import study.
    action: ACCEPT
    reason: Nuclear localization is central to both AKIRIN2 proteasome-import and transcription-coregulator biology.
    supported_by:
    - reference_id: PMID:18066067
      supporting_text: Antibody staining of the human cells clearly showed the nuclear localization of HsAkirin1 and HsAkirin2
    - reference_id: PMID:34711951
      supporting_text: nuclear import of proteasomes in vertebrates
- term:
    id: GO:0006606
    label: protein import into nucleus
  evidence_type: IDA
  original_reference_id: PMID:34711951
  qualifier: involved_in
  review:
    summary: AKIRIN2 mediates nuclear import of pre-assembled proteasome complexes.
    action: ACCEPT
    reason: This is a direct core process for the PN review because AKIRIN2 controls nuclear proteasome import.
    supported_by:
    - reference_id: PMID:34711951
      supporting_text: nuclear import of proteasomes in vertebrates
    - reference_id: PMID:34711951
      supporting_text: directly bind to fully assembled 20S proteasomes
- term:
    id: GO:0021987
    label: cerebral cortex development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: cerebral cortex development is inferred by orthology/by similarity; UniProt specifically describes a role in survival and proliferation of cerebral cortical progenitor cells.
    action: KEEP_AS_NON_CORE
    reason: Retain as a contextual developmental annotation, not as a core PN proteostasis function assignment.
    additional_reference_ids:
    - file:human/AKIRIN2/AKIRIN2-uniprot.txt
    supported_by:
    - reference_id: file:human/AKIRIN2/AKIRIN2-uniprot.txt
      supporting_text: 'Involved in brain development: required for the survival and proliferation of cerebral cortical progenitor cells'
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:34711951
  qualifier: enables
  review:
    summary: AKIRIN2 bridges assembled proteasomes and IPO9 during proteasome nuclear import, matching a protein-macromolecule adaptor role.
    action: ACCEPT
    reason: This is an appropriate core molecular-function annotation and a better functional descriptor than generic protein binding.
    supported_by:
    - reference_id: PMID:34711951
      supporting_text: directly bind to fully assembled 20S proteasomes
    - reference_id: file:human/AKIRIN2/AKIRIN2-uniprot.txt
      supporting_text: directly binds to fully assembled 20S proteasomes at one end and to nuclear import receptor IPO9 at the other end
- term:
    id: GO:0031144
    label: proteasome localization
  evidence_type: IDA
  original_reference_id: PMID:34711951
  qualifier: involved_in
  review:
    summary: AKIRIN2 is required for proteasome relocalization/import into daughter nuclei after mitosis.
    action: ACCEPT
    reason: Proteasome localization is a directly demonstrated core process for AKIRIN2.
    supported_by:
    - reference_id: PMID:34711951
      supporting_text: AKIRIN2-dependent process
    - reference_id: PMID:34711951
      supporting_text: Cells undergoing mitosis in the absence of AKIRIN2
- term:
    id: GO:0032755
    label: positive regulation of interleukin-6 production
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Mouse Akirin2 loss impairs IL-6 production downstream of TLR/IL-1R stimulation.
    action: KEEP_AS_NON_CORE
    reason: The annotation is valid as an immune transcriptional-output context, but it is not a core PN proteostasis function.
    supported_by:
    - reference_id: PMID:18066067
      supporting_text: MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation
- term:
    id: GO:0042742
    label: defense response to bacterium
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: defense response to bacterium is supported only indirectly/by orthology as an immune-system output of AKIRIN2 transcriptional regulation.
    action: KEEP_AS_NON_CORE
    reason: Keep as a contextual immune/developmental annotation, not as a core AKIRIN2 molecular function or PN proteostasis projection.
    supported_by:
    - reference_id: PMID:18066067
      supporting_text: MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation
    - reference_id: PMID:18066067
      supporting_text: Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
- term:
    id: GO:0045089
    label: positive regulation of innate immune response
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Akirin2 supports NF-kappaB-dependent innate immune gene expression in model systems, including IL-6 induction downstream of TLR/IL-1R signaling.
    action: KEEP_AS_NON_CORE
    reason: The immune-response annotation is biologically supported but represents a regulatory output context rather than the PN core proteostasis role of AKIRIN2.
    supported_by:
    - reference_id: PMID:18066067
      supporting_text: MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation
    - reference_id: PMID:18066067
      supporting_text: Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
- 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: AKIRIN2 supports NF-kappaB-dependent inducible gene expression and is conserved as a nuclear transcriptional co-regulator.
    action: ACCEPT
    reason: The process term captures a genuine AKIRIN2 transcriptional role, though it is distinct from the PN proteasome-import function.
    supported_by:
    - reference_id: PMID:18066067
      supporting_text: Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
    - reference_id: PMID:18066067
      supporting_text: Akirin is functionally and evolutionary conserved
- term:
    id: GO:0071630
    label: nuclear protein quality control by the ubiquitin-proteasome system
  evidence_type: IDA
  original_reference_id: PMID:34711951
  qualifier: acts_upstream_of_positive_effect
  review:
    summary: AKIRIN2 acts upstream of nuclear protein quality control by maintaining nuclear proteasome availability.
    action: ACCEPT
    reason: 'The qualifier is appropriate: AKIRIN2 is not a protease subunit but enables the nuclear proteasome pool needed for nuclear protein degradation.'
    supported_by:
    - reference_id: PMID:34711951
      supporting_text: nuclear protein degradation
    - reference_id: PMID:34711951
      supporting_text: accumulation of MYC and other nuclear proteins
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:23382074
  qualifier: enables
  review:
    summary: The SIRT1/enzyme-binding annotation is based on an interaction-map context and does not define a core AKIRIN2 enzymatic-adaptor function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Avoid propagating broad enzyme binding from a high-throughput interactome edge; the specific supported binding call for PN is proteasome binding.
    additional_reference_ids:
    - PMID:34711951
    supported_by:
    - reference_id: PMID:23382074
      supporting_text: high-confidence SIRT1 interactome
    - reference_id: PMID:34711951
      supporting_text: directly bind to fully assembled 20S proteasomes
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:18066067
  qualifier: located_in
  review:
    summary: AKIRIN2 is well supported as a predominantly nuclear protein by direct human localization data and by the mechanistic proteasome-import study.
    action: ACCEPT
    reason: Nuclear localization is central to both AKIRIN2 proteasome-import and transcription-coregulator biology.
    supported_by:
    - reference_id: PMID:18066067
      supporting_text: Antibody staining of the human cells clearly showed the nuclear localization of HsAkirin1 and HsAkirin2
    - reference_id: PMID:34711951
      supporting_text: nuclear import of proteasomes in vertebrates
- term:
    id: GO:0017053
    label: transcription repressor complex
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: part_of
  review:
    summary: Transcription repressor complex membership is inferred by similarity from a non-human ortholog and points to transcription-cofactor context rather than a defined human complex assignment.
    action: KEEP_AS_NON_CORE
    reason: Retain as contextual but do not treat as a core AKIRIN2 complex annotation; transcription coregulator activity captures the conserved function more cleanly.
    additional_reference_ids:
    - PMID:18066067
    supported_by:
    - reference_id: PMID:18066067
      supporting_text: Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
- term:
    id: GO:0070628
    label: proteasome binding
  evidence_type: IDA
  original_reference_id: PMID:34711951
  qualifier: enables
  review:
    summary: Proposed NEW annotation from the PN proteostasis projection, independently validated by the AKIRIN2 proteasome-import paper.
    action: NEW
    reason: The PN projection maps the proteasome-adaptor group to proteasome binding, and AKIRIN2 has direct primary evidence for binding fully assembled 20S proteasomes. This is the conservative, specific MF term that captures the PN-relevant binding event without over-claiming protease activity.
    additional_reference_ids:
    - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
    supported_by:
    - reference_id: PMID:34711951
      supporting_text: directly bind to fully assembled 20S proteasomes
    - reference_id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
      supporting_text: "AKIRIN2\t\tUbiquitin Proteasome System|Proteasome and associated proteins|adaptors|Akirin"
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: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: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  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 AKIRIN2 is a nuclear protein, and akirin proteins are conserved nuclear regulators of NF-kappaB-dependent transcription.
    supporting_text: Antibody staining of the human cells clearly showed the nuclear localization of HsAkirin1 and HsAkirin2
  - statement: Mouse Akirin2 supports TLR/IL-1R-induced IL-6 expression downstream of NF-kappaB activation.
    supporting_text: MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation
- id: PMID:23382074
  title: A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex.
  findings:
  - statement: This high-confidence SIRT1 interaction map does not establish a core AKIRIN2 enzyme-binding function.
    supporting_text: high-confidence SIRT1 interactome
- id: PMID:25180232
  title: Akirin specifies NF-kappaB selectivity of Drosophila innate immune response
    via chromatin remodeling.
  full_text_unavailable: true
  findings:
  - statement: Akirin acts as a molecular selector that confers NF-kappaB target-gene
      selectivity by recruiting an Osa-containing SWI/SNF-like (BAP) chromatin-remodeling
      complex, activating a subset of Relish-dependent immune effector genes; the
      mechanism is described as conserved to mammalian Akirin-2.
- id: PMID:26041538
  title: Essential Function for the Nuclear Protein Akirin2 in B Cell Activation and
    Humoral Immune Responses.
  full_text_unavailable: true
  findings:
  - statement: Akirin2 is required for BRG1 (SWI/SNF) recruitment to the Myc and Ccnd2
      promoters following mitogenic stimulation, supporting B-cell cycle progression,
      survival, and T-dependent and T-independent humoral immune responses.
- id: PMID:28605346
  title: Akirin2-Mediated Transcriptional Control by Recruiting SWI/SNF Complex in
    B Cells.
  full_text_unavailable: true
  findings:
  - statement: Akirin2 is an evolutionarily conserved nuclear factor that links NF-kappaB
      to chromatin remodelers, bridging signal-induced transcription factors to SWI/SNF
      complexes for selective inflammatory and B-cell gene transcription.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings:
  - statement: BioPlex/AP-MS interaction data are useful context but do not by themselves define AKIRIN2 molecular function.
    supporting_text: BioPlex 2.0 constitutes a powerful resource for biological inquiry
- id: PMID:29945498
  title: 'Expression analysis of Akirin-2, NFκB-p65 and β-catenin proteins in imatinib resistance of chronic myeloid leukemia.'
  full_text_unavailable: true
  findings:
  - statement: Increased nuclear accumulation of Akirin-2 protein was observed in
      imatinib-resistant chronic myeloid leukemia cells and proposed as a candidate
      biomarker; no direct NFkB-p65/Akirin-2 protein-protein interaction was detected
      in this system.
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: The binary interactome map provides generic physical-interaction evidence but not a specific AKIRIN2 functional assignment.
    supporting_text: reference map of the human binary protein interactome
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:34711951
  title: AKIRIN2 controls the nuclear import of proteasomes in vertebrates.
  findings:
  - statement: AKIRIN2 directly binds assembled proteasomes and mediates their nuclear import, which is the primary PN-relevant function for this review.
    supporting_text: directly bind to fully assembled 20S proteasomes
  - statement: Loss of AKIRIN2 depletes nuclear proteasomes during mitotic nuclear reassembly and impairs nuclear protein degradation.
    supporting_text: nuclear protein degradation
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: file:human/AKIRIN2/AKIRIN2-uniprot.txt
  title: UniProt text export for AKIRIN2 (Q53H80)
  findings:
  - statement: UniProt summarizes AKIRIN2 as a molecular adapter for nuclear proteasome import and as a transcriptional co-regulator in immune/developmental contexts.
    supporting_text: directly binds to fully assembled 20S proteasomes at one end and to nuclear import receptor IPO9 at the other end
- id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
  title: Proteostasis Network projected annotations report
  findings:
  - statement: The PN projection proposes proteasome binding for AKIRIN2 from the proteasome-adaptor group; this review accepts it only because direct primary evidence supports proteasome binding.
    supporting_text: "AKIRIN2\t\tUbiquitin Proteasome System|Proteasome and associated proteins|adaptors|Akirin"
- id: file:human/AKIRIN2/AKIRIN2-notes.md
  title: AKIRIN2 curator notes for Proteostasis PN review
  findings: []
core_functions:
- description: Proteasome-binding adaptor role that imports assembled proteasomes into the nucleus to maintain nuclear proteasome-dependent protein degradation.
  molecular_function:
    id: GO:0070628
    label: proteasome binding
  directly_involved_in:
  - id: GO:0006606
    label: protein import into nucleus
  - id: GO:0031144
    label: proteasome localization
  - id: GO:0071630
    label: nuclear protein quality control by the ubiquitin-proteasome system
  locations:
  - id: GO:0005634
    label: nucleus
  - id: GO:0005654
    label: nucleoplasm
  supported_by:
  - reference_id: PMID:34711951
    supporting_text: directly bind to fully assembled 20S proteasomes
  - reference_id: PMID:34711951
    supporting_text: nuclear import of proteasomes in vertebrates
  - reference_id: file:human/AKIRIN2/AKIRIN2-uniprot.txt
    supporting_text: directly binds to fully assembled 20S proteasomes at one end and to nuclear import receptor IPO9 at the other end
- description: Nuclear transcription-coregulator/adaptor role for inducible gene expression downstream of NF-kappaB and chromatin-remodeling machinery.
  molecular_function:
    id: GO:0003712
    label: transcription coregulator activity
  directly_involved_in:
  - id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  locations:
  - id: GO:0005634
    label: nucleus
  - id: GO:0000785
    label: chromatin
  supported_by:
  - reference_id: PMID:18066067
    supporting_text: Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
  - reference_id: PMID:18066067
    supporting_text: MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation
  - reference_id: file:human/AKIRIN2/AKIRIN2-uniprot.txt
    supporting_text: bridging the NF-kappa-B inhibitor NFKBIZ and the SWI/SNF complex
proposed_new_terms: []
suggested_questions:
- question: Are AKIRIN2 transcription-coregulator complexes mechanistically coupled to its nuclear proteasome-import function, or are these separable adaptor modules?
  experts:
  - de Almeida M
  - Zuber J
  - Goto A
suggested_experiments:
- hypothesis: AKIRIN2 proteasome binding and IPO9 bridging are separable from its NF-kappaB/chromatin transcription-coregulator role.
  description: Compare AKIRIN2 mutants defective in the C-terminal proteasome-binding motif with mutants affecting candidate transcription-cofactor interfaces, measuring nuclear proteasome import, MYC turnover, NF-kappaB-dependent IL6 transcription, and SWI/SNF/NFKBIZ recruitment in the same human cell system.
  experiment_type: separation-of-function mutagenesis with imaging, degradation, and transcriptional assays