Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: AKIRIN2 is well supported as a predominantly nuclear protein by direct human localization data and by the mechanistic proteasome-import study. Reason: Nuclear localization is central to both AKIRIN2 proteasome-import and transcription-coregulator biology. Supporting Evidence: PMID:18066067 Antibody staining of the human cells clearly showed the nuclear localization of HsAkirin1 and HsAkirin2 PMID:34711951 nuclear import of proteasomes in vertebrates
GO:0045089 positive regulation of innate immune response	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Akirin2 supports NF-kappaB-dependent innate immune gene expression in model systems, including IL-6 induction downstream of TLR/IL-1R signaling. Reason: The immune-response annotation is biologically supported but represents a regulatory output context rather than the PN core proteostasis role of AKIRIN2. Supporting Evidence: PMID:18066067 MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation PMID:18066067 Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
GO:0045944 positive regulation of transcription by RNA polymerase II	IBA GO_REF:0000033	ACCEPT	Summary: AKIRIN2 supports NF-kappaB-dependent inducible gene expression and is conserved as a nuclear transcriptional co-regulator. Reason: The process term captures a genuine AKIRIN2 transcriptional role, though it is distinct from the PN proteasome-import function. Supporting Evidence: PMID:18066067 Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators PMID:18066067 Akirin is functionally and evolutionary conserved
GO:0000785 chromatin	IBA GO_REF:0000033	ACCEPT	Summary: The chromatin IBA annotation is consistent with akirin function as a nuclear transcriptional cofactor associated with chromatin/transcription machinery. Reason: AKIRIN2 has a conserved nuclear transcription-coregulator role; chromatin is a reasonable active context for that role. Supporting Evidence: PMID:18066067 Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
GO:0003712 transcription coregulator activity	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:18066067 Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: AKIRIN2 is well supported as a predominantly nuclear protein by direct human localization data and by the mechanistic proteasome-import study. Reason: Nuclear localization is central to both AKIRIN2 proteasome-import and transcription-coregulator biology. Supporting Evidence: PMID:18066067 Antibody staining of the human cells clearly showed the nuclear localization of HsAkirin1 and HsAkirin2 PMID:34711951 nuclear import of proteasomes in vertebrates
GO:0005737 cytoplasm	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Cytoplasmic localization is reported by similarity and as a minor compartment in UniProt, but AKIRIN2 is predominantly nuclear. Reason: Retain as peripheral/subordinate localization rather than a primary active site for the gene product. Supporting Evidence: file:human/AKIRIN2/AKIRIN2-uniprot.txt Present mainly in the nuclear fraction, and at much lower level in the cytoplasmic and membrane fractions.
GO:0016020 membrane	IEA GO_REF:0000120	MARK AS OVER ANNOTATED	Summary: Membrane localization is by similarity and described only as a much lower-level fraction relative to the nucleus. Reason: This is likely an over-specific/peripheral localization for human AKIRIN2; the evidence does not support treating membrane as a core cellular context. Supporting Evidence: file:human/AKIRIN2/AKIRIN2-uniprot.txt Present mainly in the nuclear fraction, and at much lower level in the cytoplasmic and membrane fractions.
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	MARK AS OVER ANNOTATED	Summary: This PMID:16189514 interaction annotation records a generic high-throughput protein interaction rather than a specific AKIRIN2 activity. 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. Supporting Evidence: PMID:34711951 directly bind to fully assembled 20S proteasomes
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: This PMID:28514442 interaction annotation records a generic high-throughput protein interaction rather than a specific AKIRIN2 activity. 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. Supporting Evidence: PMID:34711951 directly bind to fully assembled 20S proteasomes
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	MARK AS OVER ANNOTATED	Summary: This PMID:31515488 interaction annotation records a generic high-throughput protein interaction rather than a specific AKIRIN2 activity. 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. Supporting Evidence: PMID:34711951 directly bind to fully assembled 20S proteasomes
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: This PMID:32296183 interaction annotation records a generic high-throughput protein interaction rather than a specific AKIRIN2 activity. 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. Supporting Evidence: PMID:34711951 directly bind to fully assembled 20S proteasomes
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: This PMID:33961781 interaction annotation records a generic high-throughput protein interaction rather than a specific AKIRIN2 activity. 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. Supporting Evidence: PMID:34711951 directly bind to fully assembled 20S proteasomes
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: This PMID:40205054 interaction annotation records a generic high-throughput protein interaction rather than a specific AKIRIN2 activity. 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. Supporting Evidence: PMID:34711951 directly bind to fully assembled 20S proteasomes
GO:0042802 identical protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	ACCEPT	Summary: The binary interactome annotation is generic, but independent mechanistic evidence shows AKIRIN2 forms homodimers. Reason: Identical protein binding is supported as a real AKIRIN2 property, although it is secondary to the proteasome-import adaptor role. Supporting Evidence: PMID:34711951 AKIRIN2 forms homodimers file:human/AKIRIN2/AKIRIN2-uniprot.txt Homodimer (PubMed:34711951)
GO:0002821 positive regulation of adaptive immune response	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: positive regulation of adaptive immune response is supported only indirectly/by orthology as an immune-system output of AKIRIN2 transcriptional regulation. Reason: Keep as a contextual immune/developmental annotation, not as a core AKIRIN2 molecular function or PN proteostasis projection. Supporting Evidence: PMID:18066067 MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation PMID:18066067 Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
GO:0009792 embryo development ending in birth or egg hatching	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: embryo development ending in birth or egg hatching is inferred from vertebrate/model-organism developmental phenotypes and is plausible for AKIRIN2 but broad. Reason: Developmental annotations should be retained as pleiotropic outcome/context terms rather than core PN function assignments. Supporting Evidence: PMID:18066067 MmAkirin2-/- mice were embryonic lethal
GO:0021987 cerebral cortex development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: cerebral cortex development is inferred by orthology/by similarity; UniProt specifically describes a role in survival and proliferation of cerebral cortical progenitor cells. Reason: Retain as a contextual developmental annotation, not as a core PN proteostasis function assignment. Supporting Evidence: file:human/AKIRIN2/AKIRIN2-uniprot.txt Involved in brain development: required for the survival and proliferation of cerebral cortical progenitor cells
GO:0030674 protein-macromolecule adaptor activity	IEA GO_REF:0000107	ACCEPT	Summary: AKIRIN2 bridges assembled proteasomes and IPO9 during proteasome nuclear import, matching a protein-macromolecule adaptor role. Reason: This is an appropriate core molecular-function annotation and a better functional descriptor than generic protein binding. Supporting Evidence: PMID:34711951 directly bind to fully assembled 20S proteasomes file:human/AKIRIN2/AKIRIN2-uniprot.txt directly binds to fully assembled 20S proteasomes at one end and to nuclear import receptor IPO9 at the other end
GO:0032755 positive regulation of interleukin-6 production	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Mouse Akirin2 loss impairs IL-6 production downstream of TLR/IL-1R stimulation. Reason: The annotation is valid as an immune transcriptional-output context, but it is not a core PN proteostasis function. Supporting Evidence: PMID:18066067 MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation
GO:0042742 defense response to bacterium	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: defense response to bacterium is supported only indirectly/by orthology as an immune-system output of AKIRIN2 transcriptional regulation. Reason: Keep as a contextual immune/developmental annotation, not as a core AKIRIN2 molecular function or PN proteostasis projection. Supporting Evidence: PMID:18066067 MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation PMID:18066067 Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
GO:0045089 positive regulation of innate immune response	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Akirin2 supports NF-kappaB-dependent innate immune gene expression in model systems, including IL-6 induction downstream of TLR/IL-1R signaling. Reason: The immune-response annotation is biologically supported but represents a regulatory output context rather than the PN core proteostasis role of AKIRIN2. Supporting Evidence: PMID:18066067 MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation PMID:18066067 Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
GO:0045944 positive regulation of transcription by RNA polymerase II	IEA GO_REF:0000107	ACCEPT	Summary: AKIRIN2 supports NF-kappaB-dependent inducible gene expression and is conserved as a nuclear transcriptional co-regulator. Reason: The process term captures a genuine AKIRIN2 transcriptional role, though it is distinct from the PN proteasome-import function. Supporting Evidence: PMID:18066067 Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators PMID:18066067 Akirin is functionally and evolutionary conserved
GO:0050871 positive regulation of B cell activation	IEA GO_REF:0000107	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:18066067 MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation PMID:18066067 Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
GO:0051147 regulation of muscle cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: regulation of muscle cell differentiation is inferred by orthology/by similarity; UniProt specifically describes a myogenesis role for AKIRIN2. Reason: Retain as a contextual developmental annotation, not as a core PN proteostasis function assignment. Supporting Evidence: file:human/AKIRIN2/AKIRIN2-uniprot.txt Involved in myogenesis: required for skeletal muscle formation and skeletal development, possibly by regulating expression of muscle differentiation factors
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: The HPA nucleoplasm annotation is consistent with the direct nuclear localization literature and AKIRIN2 function in nuclear proteasome import. Reason: Nucleoplasmic/nuclear localization is compatible with the core nuclear functions of AKIRIN2. Supporting Evidence: PMID:18066067 Antibody staining of the human cells clearly showed the nuclear localization of HsAkirin1 and HsAkirin2 PMID:34711951 nuclear import of proteasomes in vertebrates
GO:0005737 cytoplasm	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Cytoplasmic localization is reported by similarity and as a minor compartment in UniProt, but AKIRIN2 is predominantly nuclear. Reason: Retain as peripheral/subordinate localization rather than a primary active site for the gene product. Supporting Evidence: file:human/AKIRIN2/AKIRIN2-uniprot.txt Present mainly in the nuclear fraction, and at much lower level in the cytoplasmic and membrane fractions.
GO:0016020 membrane	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: Membrane localization is by similarity and described only as a much lower-level fraction relative to the nucleus. Reason: This is likely an over-specific/peripheral localization for human AKIRIN2; the evidence does not support treating membrane as a core cellular context. Supporting Evidence: file:human/AKIRIN2/AKIRIN2-uniprot.txt Present mainly in the nuclear fraction, and at much lower level in the cytoplasmic and membrane fractions.
GO:0002821 positive regulation of adaptive immune response	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: positive regulation of adaptive immune response is supported only indirectly/by orthology as an immune-system output of AKIRIN2 transcriptional regulation. Reason: Keep as a contextual immune/developmental annotation, not as a core AKIRIN2 molecular function or PN proteostasis projection. Supporting Evidence: PMID:18066067 MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation PMID:18066067 Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
GO:0005515 protein binding	IPI PMID:34711951 AKIRIN2 controls the nuclear import of proteasomes in verteb...	MODIFY	Summary: The 2021 AKIRIN2 paper supports specific proteasome and IPO9 adaptor interactions, so generic protein binding is too uninformative. 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 replacements: proteasome binding protein-macromolecule adaptor activity Supporting Evidence: PMID:34711951 directly bind to fully assembled 20S proteasomes file:human/AKIRIN2/AKIRIN2-uniprot.txt directly binds to fully assembled 20S proteasomes at one end and to nuclear import receptor IPO9 at the other end
GO:0005634 nucleus	IDA PMID:34711951 AKIRIN2 controls the nuclear import of proteasomes in verteb...	ACCEPT	Summary: AKIRIN2 is well supported as a predominantly nuclear protein by direct human localization data and by the mechanistic proteasome-import study. Reason: Nuclear localization is central to both AKIRIN2 proteasome-import and transcription-coregulator biology. Supporting Evidence: PMID:18066067 Antibody staining of the human cells clearly showed the nuclear localization of HsAkirin1 and HsAkirin2 PMID:34711951 nuclear import of proteasomes in vertebrates
GO:0006606 protein import into nucleus	IDA PMID:34711951 AKIRIN2 controls the nuclear import of proteasomes in verteb...	ACCEPT	Summary: AKIRIN2 mediates nuclear import of pre-assembled proteasome complexes. Reason: This is a direct core process for the PN review because AKIRIN2 controls nuclear proteasome import. Supporting Evidence: PMID:34711951 nuclear import of proteasomes in vertebrates PMID:34711951 directly bind to fully assembled 20S proteasomes
GO:0021987 cerebral cortex development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: cerebral cortex development is inferred by orthology/by similarity; UniProt specifically describes a role in survival and proliferation of cerebral cortical progenitor cells. Reason: Retain as a contextual developmental annotation, not as a core PN proteostasis function assignment. Supporting Evidence: file:human/AKIRIN2/AKIRIN2-uniprot.txt Involved in brain development: required for the survival and proliferation of cerebral cortical progenitor cells
GO:0030674 protein-macromolecule adaptor activity	IDA PMID:34711951 AKIRIN2 controls the nuclear import of proteasomes in verteb...	ACCEPT	Summary: AKIRIN2 bridges assembled proteasomes and IPO9 during proteasome nuclear import, matching a protein-macromolecule adaptor role. Reason: This is an appropriate core molecular-function annotation and a better functional descriptor than generic protein binding. Supporting Evidence: PMID:34711951 directly bind to fully assembled 20S proteasomes file:human/AKIRIN2/AKIRIN2-uniprot.txt directly binds to fully assembled 20S proteasomes at one end and to nuclear import receptor IPO9 at the other end
GO:0031144 proteasome localization	IDA PMID:34711951 AKIRIN2 controls the nuclear import of proteasomes in verteb...	ACCEPT	Summary: AKIRIN2 is required for proteasome relocalization/import into daughter nuclei after mitosis. Reason: Proteasome localization is a directly demonstrated core process for AKIRIN2. Supporting Evidence: PMID:34711951 AKIRIN2-dependent process PMID:34711951 Cells undergoing mitosis in the absence of AKIRIN2
GO:0032755 positive regulation of interleukin-6 production	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Mouse Akirin2 loss impairs IL-6 production downstream of TLR/IL-1R stimulation. Reason: The annotation is valid as an immune transcriptional-output context, but it is not a core PN proteostasis function. Supporting Evidence: PMID:18066067 MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation
GO:0042742 defense response to bacterium	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: defense response to bacterium is supported only indirectly/by orthology as an immune-system output of AKIRIN2 transcriptional regulation. Reason: Keep as a contextual immune/developmental annotation, not as a core AKIRIN2 molecular function or PN proteostasis projection. Supporting Evidence: PMID:18066067 MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation PMID:18066067 Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
GO:0045089 positive regulation of innate immune response	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Akirin2 supports NF-kappaB-dependent innate immune gene expression in model systems, including IL-6 induction downstream of TLR/IL-1R signaling. Reason: The immune-response annotation is biologically supported but represents a regulatory output context rather than the PN core proteostasis role of AKIRIN2. Supporting Evidence: PMID:18066067 MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation PMID:18066067 Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
GO:0045944 positive regulation of transcription by RNA polymerase II	ISS GO_REF:0000024	ACCEPT	Summary: AKIRIN2 supports NF-kappaB-dependent inducible gene expression and is conserved as a nuclear transcriptional co-regulator. Reason: The process term captures a genuine AKIRIN2 transcriptional role, though it is distinct from the PN proteasome-import function. Supporting Evidence: PMID:18066067 Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators PMID:18066067 Akirin is functionally and evolutionary conserved
GO:0071630 nuclear protein quality control by the ubiquitin-proteasome system	IDA PMID:34711951 AKIRIN2 controls the nuclear import of proteasomes in verteb...	ACCEPT	Summary: AKIRIN2 acts upstream of nuclear protein quality control by maintaining nuclear proteasome availability. Reason: The qualifier is appropriate: AKIRIN2 is not a protease subunit but enables the nuclear proteasome pool needed for nuclear protein degradation. Supporting Evidence: PMID:34711951 nuclear protein degradation PMID:34711951 accumulation of MYC and other nuclear proteins
GO:0019899 enzyme binding	IPI PMID:23382074 A high-confidence interaction map identifies SIRT1 as a medi...	MARK AS OVER ANNOTATED	Summary: The SIRT1/enzyme-binding annotation is based on an interaction-map context and does not define a core AKIRIN2 enzymatic-adaptor function. Reason: Avoid propagating broad enzyme binding from a high-throughput interactome edge; the specific supported binding call for PN is proteasome binding. Supporting Evidence: PMID:23382074 high-confidence SIRT1 interactome PMID:34711951 directly bind to fully assembled 20S proteasomes
GO:0005634 nucleus	IDA PMID:18066067 Akirins are highly conserved nuclear proteins required for N...	ACCEPT	Summary: AKIRIN2 is well supported as a predominantly nuclear protein by direct human localization data and by the mechanistic proteasome-import study. Reason: Nuclear localization is central to both AKIRIN2 proteasome-import and transcription-coregulator biology. Supporting Evidence: PMID:18066067 Antibody staining of the human cells clearly showed the nuclear localization of HsAkirin1 and HsAkirin2 PMID:34711951 nuclear import of proteasomes in vertebrates
GO:0017053 transcription repressor complex	ISS GO_REF:0000024	KEEP AS NON CORE	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. Reason: Retain as contextual but do not treat as a core AKIRIN2 complex annotation; transcription coregulator activity captures the conserved function more cleanly. Supporting Evidence: PMID:18066067 Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
GO:0070628 proteasome binding	IDA PMID:34711951 AKIRIN2 controls the nuclear import of proteasomes in verteb...	NEW	Summary: Proposed NEW annotation from the PN proteostasis projection, independently validated by the AKIRIN2 proteasome-import paper. 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. Supporting Evidence: PMID:34711951 directly bind to fully assembled 20S proteasomes file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv AKIRIN2 Ubiquitin Proteasome System\|Proteasome and associated proteins\|adaptors\|Akirin

Core Functions

Proteasome-binding adaptor role that imports assembled proteasomes into the nucleus to maintain nuclear proteasome-dependent protein degradation.

Molecular Function:

proteasome binding

Directly Involved In:

protein import into nucleus proteasome localization nuclear protein quality control by the ubiquitin-proteasome system

Cellular Locations:

nucleus nucleoplasm

Supporting Evidence:

PMID:34711951
directly bind to fully assembled 20S proteasomes
PMID:34711951
nuclear import of proteasomes in vertebrates
file:human/AKIRIN2/AKIRIN2-uniprot.txt
directly binds to fully assembled 20S proteasomes at one end and to nuclear import receptor IPO9 at the other end

Nuclear transcription-coregulator/adaptor role for inducible gene expression downstream of NF-kappaB and chromatin-remodeling machinery.

Molecular Function:

transcription coregulator activity

Directly Involved In:

positive regulation of transcription by RNA polymerase II

Cellular Locations:

nucleus chromatin

Supporting Evidence:

PMID:18066067
Akirins are novel important nuclear cofactors regulating the transcriptional activities of main transactivators
PMID:18066067
MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation
file:human/AKIRIN2/AKIRIN2-uniprot.txt
bridging the NF-kappa-B inhibitor NFKBIZ and the SWI/SNF complex

References

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:16189514

Towards a proteome-scale map of the human protein-protein interaction network.

PMID:18066067

Akirins are highly conserved nuclear proteins required for NF-kappaB-dependent gene expression in drosophila and mice.

Human AKIRIN2 is a nuclear protein, and akirin proteins are conserved nuclear regulators of NF-kappaB-dependent transcription.

"Antibody staining of the human cells clearly showed the nuclear localization of HsAkirin1 and HsAkirin2"
Mouse Akirin2 supports TLR/IL-1R-induced IL-6 expression downstream of NF-kappaB activation.

"MmAkirin2, but not MmAkirin1, was responsible for the production of IL-6 in response to TLR or IL-1R stimulation"

PMID:23382074

A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex.

This high-confidence SIRT1 interaction map does not establish a core AKIRIN2 enzyme-binding function.

"high-confidence SIRT1 interactome"

PMID:25180232

Akirin specifies NF-kappaB selectivity of Drosophila innate immune response via chromatin remodeling.

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.

PMID:26041538

Essential Function for the Nuclear Protein Akirin2 in B Cell Activation and Humoral Immune Responses.

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.

PMID:28605346

Akirin2-Mediated Transcriptional Control by Recruiting SWI/SNF Complex in B Cells.

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.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

BioPlex/AP-MS interaction data are useful context but do not by themselves define AKIRIN2 molecular function.

"BioPlex 2.0 constitutes a powerful resource for biological inquiry"

PMID:29945498

Expression analysis of Akirin-2, NFκB-p65 and β-catenin proteins in imatinib resistance of chronic myeloid leukemia.

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.

PMID:31515488

Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.

PMID:32296183

A reference map of the human binary protein interactome.

The binary interactome map provides generic physical-interaction evidence but not a specific AKIRIN2 functional assignment.

"reference map of the human binary protein interactome"

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:34711951

AKIRIN2 controls the nuclear import of proteasomes in vertebrates.

AKIRIN2 directly binds assembled proteasomes and mediates their nuclear import, which is the primary PN-relevant function for this review.

"directly bind to fully assembled 20S proteasomes"
Loss of AKIRIN2 depletes nuclear proteasomes during mitotic nuclear reassembly and impairs nuclear protein degradation.

"nuclear protein degradation"

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

file:human/AKIRIN2/AKIRIN2-uniprot.txt

UniProt text export for AKIRIN2 (Q53H80)

UniProt summarizes AKIRIN2 as a molecular adapter for nuclear proteasome import and as a transcriptional co-regulator in immune/developmental contexts.

"directly binds to fully assembled 20S proteasomes at one end and to nuclear import receptor IPO9 at the other end"

file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv

Proteostasis Network projected annotations report

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.

"AKIRIN2 Ubiquitin Proteasome System|Proteasome and associated proteins|adaptors|Akirin"

file:human/AKIRIN2/AKIRIN2-notes.md

AKIRIN2 curator notes for Proteostasis PN review

Suggested Experiments

Experiment: 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.

Hypothesis: AKIRIN2 proteasome binding and IPO9 bridging are separable from its NF-kappaB/chromatin transcription-coregulator role.

Type: separation-of-function mutagenesis with imaging, degradation, and transcriptional assays

Deep Research

Falcon

(AKIRIN2-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 19 citations 2 artifacts 2026-06-07T04:23:06.578287

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000015 Figure 5C in the document provides a list of uniquely liganded cysteines, including AKIRIN2 (Akirin-2) Cys3, as part of a heat map (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: Human AKIRIN2 (Akirin-2; UniProt Q53H80, gene symbol AKIRIN2; synonym C6orf166) — functional annotation

0) Mandatory identity verification (disambiguation)

The target protein is human Akirin-2, encoded by AKIRIN2 (synonym C6orf166) and assigned to the akirin protein family (UniProt accession Q53H80, per user-provided context). The literature retrieved here is consistent with an evolutionarily conserved, primarily nuclear, non-enzymatic transcriptional cofactor/adaptor termed Akirin2/Akirin-2 (mammals) and Akirin (invertebrates), which lacks an obvious DNA-binding motif and functions via protein–protein interactions to connect signaling-dependent transcription factors (notably NF-κB pathway outputs) to chromatin remodeling machinery (tartey2016akirin2mediatedtranscriptionalcontrol pages 5-6, tartey2016akirin2mediatedtranscriptionalcontrol pages 1-2, tartey2016akirin2mediatedtranscriptionalcontrol pages 6-8).

Scope note: Much mechanistic evidence comes from mouse immune cells and Drosophila; these are used to infer human function because the mechanism is described as conserved and directly discussed in the mammalian Akirin2 context (tartey2016akirin2mediatedtranscriptionalcontrol pages 5-6, bonnay2014akirinspecifiesnfκb pages 2-3).

1) Key concepts and definitions (current understanding)

1.1 What AKIRIN2 is (functional class)

AKIRIN2 is best understood as a signal-responsive transcriptional cofactor/adaptor rather than an enzyme, receptor, or transporter. It is described as a highly conserved nuclear protein required for NF-κB-dependent gene expression, but importantly it contributes to selective induction of a subset of NF-κB target genes rather than serving as a universal NF-κB co-activator (tartey2016akirin2mediatedtranscriptionalcontrol pages 5-6, tartey2016akirin2mediatedtranscriptionalcontrol pages 10-11).

Mechanistically, AKIRIN2 is described as linking transcriptional programs to chromatin remodeling, particularly SWI/SNF (BAF) complexes (tartey2016akirin2mediatedtranscriptionalcontrol pages 1-2, tartey2016akirin2mediatedtranscriptionalcontrol pages 6-8).

1.2 “NF-κB selectivity” and “chromatin remodeling bridge”

A recurring concept is that Akirin proteins confer NF-κB target gene selectivity by enabling recruitment of SWI/SNF remodelers at specific promoters. In Drosophila, Akirin physically connects the NF-κB transcription factor Relish with the SWI/SNF component BAP60, supporting a promoter-bound complex that preferentially activates a subset of immune effector genes (bonnay2014akirinspecifiesnfκb pages 9-11, bonnay2014akirinspecifiesnfκb pages 2-3). The mechanism is presented as evolutionarily conserved, with mammalian Akirin-2 binding BAF60 homologs (bonnay2014akirinspecifiesnfκb pages 9-11).

1.3 Protein features relevant to function

Akirin2 is summarized as lacking obvious DNA-binding motifs, with regions consistent with protein–protein interaction roles (including conserved helical regions), and having an N-terminal nuclear localization signal, consistent with its nuclear cofactor role (tartey2016akirin2mediatedtranscriptionalcontrol pages 5-6).

2) Experimentally supported functions, pathways, partners, and localization

2.1 Core molecular function: adaptor linking NF-κB/IκBζ to SWI/SNF (BAF)

A major experimentally supported model is that Akirin2 helps drive transcription of specific inflammatory genes by bridging NF-κB pathway components to SWI/SNF chromatin remodelers (tartey2016akirin2mediatedtranscriptionalcontrol pages 1-2, tartey2016akirin2mediatedtranscriptionalcontrol pages 10-11).

IκBζ (NFKBIZ)–Akirin2–SWI/SNF axis: In macrophage contexts, IκBζ is reported to bind Akirin2 (via Akirin2’s C-terminal region) and to cooperate with Akirin2 and Brg1 (SWI/SNF) to support promoter recruitment and activation of inflammatory genes including Il6 and Il12b after innate immune stimulation (e.g., LPS/IL-1β/TLR signaling) (tartey2016akirin2mediatedtranscriptionalcontrol pages 6-8, tartey2016akirin2mediatedtranscriptionalcontrol pages 10-11).

This places AKIRIN2 within the nuclear stage of NF-κB response, acting downstream of receptor signaling to implement chromatin remodeling–dependent transcriptional programs (tartey2016akirin2mediatedtranscriptionalcontrol pages 5-6, tartey2016akirin2mediatedtranscriptionalcontrol pages 6-8).

2.2 Immune-cell biology: B cell activation programs

In B cells, Akirin2 is described as required for recruitment of Brg1 to promoters such as Myc and Ccnd2 after CD40 stimulation, supporting expression of proliferative and survival genes (e.g., Myc, Ccnd1/2, Bcl2, Bcl-xL) and thereby influencing B-cell proliferation/survival and antibody responses (tartey2016akirin2mediatedtranscriptionalcontrol pages 6-8, tartey2016akirin2mediatedtranscriptionalcontrol pages 8-10).

2.3 Developmental essentiality (strong genetic evidence from mouse)

Akirin2 is described as essential for embryonic development, with knockout lethality by embryonic day E9.5 in mice, consistent with a fundamental role in transcriptional regulation (tartey2016akirin2mediatedtranscriptionalcontrol pages 5-6).

2.4 Promoter-context selectivity (epigenetic logic)

Akirin2-dependent genes are summarized as enriched among promoters with lower CpG-island density, suggesting that some promoters may require Akirin2-dependent SWI/SNF remodeling for activation, providing one mechanistic explanation for selective NF-κB gene induction (tartey2016akirin2mediatedtranscriptionalcontrol pages 5-6, tartey2016akirin2mediatedtranscriptionalcontrol pages 6-8).

2.5 Subcellular localization

Akirin2 is repeatedly described as nuclear in mechanistic reviews, consistent with its role in transcriptional control and chromatin remodeling (tartey2016akirin2mediatedtranscriptionalcontrol pages 5-6, tartey2016akirin2mediatedtranscriptionalcontrol pages 1-2, tartey2016akirin2mediatedtranscriptionalcontrol pages 10-11). In a cancer drug-resistance context (CML), increased nuclear accumulation of Akirin-2 in imatinib-resistant cells was reported (without numeric fold-change in retrieved excerpts) (karabay2018expressionanalysisof pages 7-7).

3) Recent developments (prioritizing 2023–2024)

3.1 2024 chemoproteomics: a newly observed ligandable cysteine in AKIRIN2

A 2024 chemoproteomics study (Burton & Backus, Communications Chemistry, published Apr 2024; https://doi.org/10.1038/s42004-024-01162-x) reported AKIRIN2 Cys3 among “uniquely liganded” cysteines detected by their sCIP-TMT workflow, and noted this residue is proximal to a 20S proteasome binding motif (burton2024functionalizingtandemmass pages 5-7).

Quantitatively in that dataset: they report 29 uniquely liganded cysteines in the study; and that 760/789 liganded cysteines had prior support in CysDB, highlighting that AKIRIN2 Cys3 belonged to a small set of newly observed ligandable sites (burton2024functionalizingtandemmass pages 5-7). Figure evidence for AKIRIN2 Cys3 being listed among uniquely liganded cysteines is shown in their Figure 5C (burton2024functionalizingtandemmass media b5b8243d, burton2024functionalizingtandemmass media 0c97aa47).

Interpretation: This is not direct functional enzymology (AKIRIN2 is not an enzyme) but provides chemical tractability/ligandability data that could enable future chemical biology tools (burton2024functionalizingtandemmass pages 5-7).

3.2 2024 transcriptional meta-analysis: AKIRIN2 as a conditional NRF2-responsive gene

A 2024 study (Luo et al., Antioxidants & Redox Signaling, Dec 2024; https://doi.org/10.1089/ars.2023.0409) derived a “core NRF2” transcriptional signature from seven RNA-seq datasets and reported that AKIRIN2 was primarily upregulated in drug-mediated NRF2 activation contexts, but not consistently upregulated in some cancer cohort/cell line datasets (e.g., TCGA LUAD/NSCLC analyses mentioned in the excerpt) (luo2024acorenrf2 pages 4-7).

Interpretation: This supports AKIRIN2 as a context-dependent oxidative-stress/Nrf2-responsive transcript in some settings, but does not by itself establish direct NRF2 binding at AKIRIN2 regulatory elements (luo2024acorenrf2 pages 4-7).

3.3 2023–2024 updates on the IκBζ axis (contextual, not AKIRIN2-specific in retrieved excerpt)

A 2024 review on IκBζ (Yamazaki, Cells, Aug 2024; https://doi.org/10.3390/cells13171467) reinforces that IκBζ supports selective NF-κB target gene induction through SWI/SNF-dependent chromatin remodeling (including examples such as IL6/LCN2 and dependence on BRG1 recruitment), which is mechanistically consistent with the previously described IκBζ–Akirin2–SWI/SNF framework (yamazaki2024thenuclearnfκb pages 4-6). However, the retrieved excerpt does not explicitly mention Akirin2/AKIRIN2 by name, so it mainly strengthens the pathway background rather than directly updating AKIRIN2-specific mechanisms (yamazaki2024thenuclearnfκb pages 4-6).

4) Current applications and real-world implementations

4.1 Translational relevance: cancer-associated expression and resistance phenotypes

AKIRIN2 has been linked to tumor phenotypes in multiple models. A review summary describes Akirin2 as implicated as an oncogene and notes overexpression in tumor cell lines, where knockdown/antisense approaches reduced growth/tumorigenicity/metastasis in models and increased cell death susceptibility in glioblastoma lines (tartey2016akirin2mediatedtranscriptionalcontrol pages 5-6). In chronic myeloid leukemia models, increased nuclear accumulation of Akirin-2 in imatinib-resistant cells was proposed as a potential biomarker (karabay2018expressionanalysisof pages 7-7).

Implementation status: These are primarily preclinical or biomarker-proposal level findings; no AKIRIN2-targeted therapy is established in the retrieved evidence.

4.2 Chemical biology opportunity: ligandability at Cys3

The 2024 sCIP-TMT chemoproteomics finding (AKIRIN2 Cys3 ligandability) provides a practical foothold for developing covalent probes to interrogate AKIRIN2 function or interactions in cells (burton2024functionalizingtandemmass pages 5-7, burton2024functionalizingtandemmass media b5b8243d).

4.3 Systems biology signatures: NRF2 activation scoring

The 2024 NRF2 signature work includes AKIRIN2 as a conditional NRF2-induced gene in drug-activation settings, implying AKIRIN2 may appear in transcriptomic readouts of oxidative-stress responses in some perturbation screens (luo2024acorenrf2 pages 4-7).

5) Expert opinions / authoritative synthesis

A focused immunology review explicitly frames Akirin2 as a central nuclear cofactor that mediates transcriptional programs by recruiting SWI/SNF chromatin remodeling, emphasizing its role as a bridge linking signaling-induced transcription factors to chromatin remodeling machinery and driving selective NF-κB-dependent transcription (Tartey & Takeuchi, Crit Rev Immunol, Jan 2016, https://doi.org/10.1615/critrevimmunol.2017019629) (tartey2016akirin2mediatedtranscriptionalcontrol pages 1-2, tartey2016akirin2mediatedtranscriptionalcontrol pages 10-11). Although not new, this remains one of the clearest authoritative mechanistic syntheses in the retrieved corpus.

A key conceptual advance from the Drosophila EMBO Journal study is the “molecular selector” model—Akirin defining NF-κB target subset choice via chromatin remodeling—explicitly presented as conserved in mammals, supporting its relevance to human AKIRIN2 annotation (Bonnay et al., EMBO J, Sep 2014, https://doi.org/10.15252/embj.201488456) (bonnay2014akirinspecifiesnfκb pages 9-11, bonnay2014akirinspecifiesnfκb pages 2-3).

6) Relevant statistics and quantitative findings (from retrieved recent and foundational studies)

Gene selectivity (Drosophila): Akirin required for 9 of 41 Relish-dependent immune-related genes; Akirin alone required for activation of 31 genes independently of Relish; loss caused derepression/overexpression of 205 genes (Bonnay et al. 2014) (bonnay2014akirinspecifiesnfκb pages 2-3).
Chemoproteomics coverage (2024): 29 uniquely liganded cysteines identified in the sCIP-TMT study; 760/789 liganded cysteines had prior identification in CysDB; AKIRIN2 Cys3 was among “previously unreported liganded sites” (Burton & Backus 2024) (burton2024functionalizingtandemmass pages 5-7).
NRF2 signature construction (2024): Seven transcriptomic datasets generated/analyzed to derive a candidate core NRF2 gene set; AKIRIN2 highlighted as conditionally induced in drug-mediated NRF2 activation but not consistently across LUAD/NSCLC datasets described in excerpt (Luo et al. 2024) (luo2024acorenrf2 pages 4-7).

Consolidated evidence table

Functional claim	Mechanism/partners/pathway	Cell/tissue/model	Key experimental evidence type	Quantitative/statistical detail (if available)	Primary source with publication date and URL/DOI	Notes (strength/limitations/species ambiguity)
Human AKIRIN2 (UniProt Q53H80) is the conserved nuclear Akirin-2 protein in the akirin family and functions primarily as a transcriptional cofactor rather than a DNA-binding enzyme or receptor	Lacks obvious DNA/RNA-binding motifs; contains N-terminal nuclear localization signal and conserved helical regions; acts through protein-protein interactions to couple NF-κB-responsive factors to chromatin remodeling machinery	Mammals/human ortholog context summarized from mouse and immune-cell studies	Review synthesis of KO/knockdown, promoter studies, interaction studies	Mouse Akirin2 knockout causes embryonic lethality by E9.5	Tartey & Takeuchi, Crit Rev Immunol (Jan 2016), https://doi.org/10.1615/CritRevImmunol.2017019629 (tartey2016akirin2mediatedtranscriptionalcontrol pages 5-6, tartey2016akirin2mediatedtranscriptionalcontrol pages 1-2)	Strong mechanistic review grounded in primary studies; some evidence is from mouse rather than direct human experiments
AKIRIN2 is required for selective, not global, NF-κB-dependent transcription	Bridges NF-κB pathway output to SWI/SNF (BAF/Brg1) chromatin remodeling, enabling induction of specific inflammatory genes after TLR/IL-1/TNF signaling	Mouse embryonic fibroblasts, macrophages, B cells	Genetic KO/conditional deletion, promoter recruitment, transcriptional analysis	Selective defect in a subset of inducible genes rather than pan-NF-κB failure; promoters with lower CpG-island density are enriched among Akirin2-dependent genes	Tartey & Takeuchi, Crit Rev Immunol (Jan 2016), https://doi.org/10.1615/CritRevImmunol.2017019629 (tartey2016akirin2mediatedtranscriptionalcontrol pages 5-6, tartey2016akirin2mediatedtranscriptionalcontrol pages 6-8, tartey2016akirin2mediatedtranscriptionalcontrol pages 8-10, tartey2016akirin2mediatedtranscriptionalcontrol pages 10-11)	High-value functional annotation for human AKIRIN2 by orthology/conservation; quantitative fold changes were not provided in the retrieved excerpts
AKIRIN2 cooperates with IκBζ (NFKBIZ) and SWI/SNF to activate inflammatory promoters	IκBζ binds the C-terminal region of Akirin2; IκBζ-Akirin2-SWI/SNF complex interacts with NF-κB p50 and supports recruitment to Il6 and Il12b promoters after LPS/IL-1β/TLR stimulation	Macrophages	ChIP/recruitment studies, interaction mapping, stimulus-response transcription assays	No numeric recruitment values in retrieved excerpt; mechanistic link reported for Il6 and Il12b promoters	Tartey & Takeuchi, Crit Rev Immunol (Jan 2016), https://doi.org/10.1615/CritRevImmunol.2017019629 (tartey2016akirin2mediatedtranscriptionalcontrol pages 6-8, tartey2016akirin2mediatedtranscriptionalcontrol pages 10-11)	Strong pathway-specific mechanism; evidence is largely from mouse/immune-cell literature but directly relevant to conserved human AKIRIN2 function
AKIRIN2 supports B-cell activation and survival programs	Required for Brg1 recruitment to Myc and Ccnd2 promoters after CD40 stimulation; supports expression of Myc, Ccnd1, Ccnd2, Bcl2 and Bcl-xL	B cells	Conditional deletion, promoter recruitment, transcriptional profiling	Loss of Akirin2 severely impairs T-cell-dependent and T-cell-independent antibody responses; decreased splenic follicular and marginal zone B cells	Tartey & Takeuchi, Crit Rev Immunol (Jan 2016), https://doi.org/10.1615/CritRevImmunol.2017019629 (tartey2016akirin2mediatedtranscriptionalcontrol pages 6-8, tartey2016akirin2mediatedtranscriptionalcontrol pages 8-10)	Useful for immune-function annotation; retrieved evidence did not include exact cell-count statistics
Akirin proteins act as molecular selectors that confer NF-κB target-gene specificity through chromatin remodeling, a mechanism conserved to mammals	In Drosophila, Akirin binds Relish and BAP60 (SWI/SNF/BAP), forming a bridge to remodel chromatin at selected promoters; authors note conservation with mouse Akirin-2 binding BAF60 homologs	Drosophila innate immune system with mammalian conservation inference	Genome-wide expression analysis, proteomics, interaction studies, infection phenotyping	Akirin required for 9 of 41 Relish-dependent immune-related genes; Akirin alone required for 31 genes independently of Relish; loss caused derepression/overexpression of 205 genes	Bonnay et al., EMBO Journal (Sep 2014), https://doi.org/10.15252/embj.201488456 (bonnay2014akirinspecifiesnfκb pages 9-11, bonnay2014akirinspecifiesnfκb pages 2-3)	Not human-specific, but highly informative for conserved Akirin biology; should be used as evolutionary/mechanistic support, not as sole human evidence
AKIRIN2 contains a newly observed ligandable cysteine near a proteasome-related motif, suggesting potential chemical tractability	Chemoproteomics identified AKIRIN2 Cys3 as a uniquely liganded cysteine; text notes proximity to the 20S proteasome binding motif	Human proteome-scale chemoproteomics dataset	Chemoproteomics (sCIP-TMT), Figure 5C	29 uniquely liganded cysteines identified in study; 760/789 liganded cysteines had prior CysDB support, placing AKIRIN2 Cys3 among newly observed sites	Burton & Backus, Communications Chemistry (Apr 2024), https://doi.org/10.1038/s42004-024-01162-x (burton2024functionalizingtandemmass pages 5-7, burton2024functionalizingtandemmass media b5b8243d, burton2024functionalizingtandemmass media 0c97aa47)	Important recent finding, but it does not establish AKIRIN2 biochemical function or therapeutic efficacy; ligandability ≠ validated drug target
AKIRIN2 can behave as a conditional NRF2-responsive gene in some pharmacologic activation contexts	AKIRIN2 was induced mainly in drug-mediated NRF2 activation datasets, but not consistently in TCGA LUAD or NSCLC cell-line analyses; thus not part of the most universal core NRF2 output	Multiple transcriptomic datasets including pharmacologic CDDO-2P-Im treatment and genetic KEAP1-knockout models	RNA-seq / transcriptomic meta-analysis	Seven transcriptomic databases used to derive a 15-gene candidate NRF2 core set; AKIRIN2 highlighted as conditionally induced rather than universally upregulated	Luo et al., Antioxidants & Redox Signaling (Dec 2024), https://doi.org/10.1089/ars.2023.0409 (luo2024acorenrf2 pages 4-7)	Recent and useful for regulatory context; this is association/expression evidence, not proof of direct NRF2 binding to AKIRIN2 regulatory DNA
2024 IκBζ review reinforces the SWI/SNF-dependent selective NF-κB transcription mechanism relevant to AKIRIN2, but the retrieved excerpt does not explicitly mention Akirin2	IκBζ promotes BRG1/SWI/SNF recruitment and chromatin remodeling at secondary NF-κB target genes such as IL6/LCN2, with p50 preference and promoter motif selectivity	Inflammatory gene regulation context	Review synthesis of ChIP/ATAC/structural studies	BRG1 recruitment to Lcn2 promoter is abolished without IκBζ; no AKIRIN2-specific quantitative measure in excerpt	Yamazaki, Cells (Aug 2024), https://doi.org/10.3390/cells13171467 (yamazaki2024thenuclearnfκb pages 4-6)	Useful contextual support for the IκBζ arm of the pathway; limitation: excerpt did not directly mention AKIRIN2, so it supports pathway context more than direct annotation
FBI1/Akirin2 has tumor-related functions in liver-cancer models, but this evidence is not specific to human AKIRIN2 and should be interpreted cautiously	Reported as a 14-3-3β-binding protein that sustains ERK1/2 activation by suppressing MKP-1; silencing FBI1/Akirin2 increases Lu/BCAM expression, consistent with Lu/BCAM as a possible downstream target	Rat hepatoma / rat liver cancer cells	Review citing functional silencing/overexpression studies	No exact effect sizes in retrieved excerpt; claim is qualitative (increased Lu/BCAM on Akirin2 silencing; reduced colony formation/migration/invasion with Lu/BCAM overexpression)	Jin et al., Int J Mol Sci (Jul 2024), https://doi.org/10.3390/ijms25137268 (jin2024theroleof pages 5-6, jin2024theroleof pages 8-10)	Important caveat: these findings concern rat cells/ortholog context and FBI1 alias usage; not sufficient alone for direct human AKIRIN2 functional annotation
AKIRIN2 has been implicated in cancer-associated phenotypes and nuclear accumulation in resistance states	Conserved nuclear NF-κB cofactor; increased nuclear AKIRIN2 reported in imatinib-resistant CML cells; related literature links AKIRIN2/FBI1 to tumorigenicity/metastasis and glioblastoma chemosensitivity	Human CML cells; broader tumor-cell literature summarized	Expression analysis, nuclear protein localization, literature synthesis	Increased nuclear accumulation in resistant cells reported, but no exact fold-change in retrieved excerpt	Karabay et al., Hematology (Jun 2018), https://doi.org/10.1080/10245332.2018.1488795 (karabay2018expressionanalysisof pages 7-7)	Human disease relevance is suggestive, but this is downstream/association-heavy and not the strongest source for core molecular function

Table: This table summarizes experimentally supported and recent literature-based functional annotation evidence for human AKIRIN2 (UniProt Q53H80), including core mechanism, pathway context, localization/function in immune transcription, and recent 2024 omics/chemoproteomics findings. It also flags species and evidence-strength limitations where the literature is indirect or ortholog-based.

Conclusion (functional annotation summary)

Across mechanistic immunology literature and conserved invertebrate models, the primary function of human AKIRIN2 (Akirin-2; Q53H80) is best annotated as a nuclear transcriptional cofactor/adaptor that confers selective activation of NF-κB-dependent gene programs by partnering with IκBζ (NFKBIZ) and recruiting SWI/SNF (BAF/BRG1) chromatin remodeling complexes to specific promoters (tartey2016akirin2mediatedtranscriptionalcontrol pages 6-8, tartey2016akirin2mediatedtranscriptionalcontrol pages 10-11). Recent 2024 work extends AKIRIN2’s practical research relevance by identifying AKIRIN2 Cys3 as a ligandable site in human proteome chemoproteomics (potential for probe development) and by situating AKIRIN2 as a context-dependent NRF2-responsive gene in pharmacologic activation datasets (burton2024functionalizingtandemmass pages 5-7, luo2024acorenrf2 pages 4-7).

References

(tartey2016akirin2mediatedtranscriptionalcontrol pages 5-6): Sarang Tartey and Osamu Takeuchi. Akirin2-mediated transcriptional control by recruiting swi/snf complex in b cells. Critical reviews in immunology, 36 5:395-406, Jan 2016. URL: https://doi.org/10.1615/critrevimmunol.2017019629, doi:10.1615/critrevimmunol.2017019629. This article has 8 citations and is from a peer-reviewed journal.
(tartey2016akirin2mediatedtranscriptionalcontrol pages 1-2): Sarang Tartey and Osamu Takeuchi. Akirin2-mediated transcriptional control by recruiting swi/snf complex in b cells. Critical reviews in immunology, 36 5:395-406, Jan 2016. URL: https://doi.org/10.1615/critrevimmunol.2017019629, doi:10.1615/critrevimmunol.2017019629. This article has 8 citations and is from a peer-reviewed journal.
(tartey2016akirin2mediatedtranscriptionalcontrol pages 6-8): Sarang Tartey and Osamu Takeuchi. Akirin2-mediated transcriptional control by recruiting swi/snf complex in b cells. Critical reviews in immunology, 36 5:395-406, Jan 2016. URL: https://doi.org/10.1615/critrevimmunol.2017019629, doi:10.1615/critrevimmunol.2017019629. This article has 8 citations and is from a peer-reviewed journal.
(bonnay2014akirinspecifiesnfκb pages 2-3): François Bonnay, Xuan‐Hung Nguyen, Eva Cohen‐Berros, Laurent Troxler, Eric Batsche, Jacques Camonis, Osamu Takeuchi, Jean‐Marc Reichhart, and Nicolas Matt. Akirin specifies nf-κb selectivity of drosophila innate immune response via chromatin remodeling. The EMBO Journal, 33:2349-2362, Sep 2014. URL: https://doi.org/10.15252/embj.201488456, doi:10.15252/embj.201488456. This article has 124 citations.
(tartey2016akirin2mediatedtranscriptionalcontrol pages 10-11): Sarang Tartey and Osamu Takeuchi. Akirin2-mediated transcriptional control by recruiting swi/snf complex in b cells. Critical reviews in immunology, 36 5:395-406, Jan 2016. URL: https://doi.org/10.1615/critrevimmunol.2017019629, doi:10.1615/critrevimmunol.2017019629. This article has 8 citations and is from a peer-reviewed journal.
(bonnay2014akirinspecifiesnfκb pages 9-11): François Bonnay, Xuan‐Hung Nguyen, Eva Cohen‐Berros, Laurent Troxler, Eric Batsche, Jacques Camonis, Osamu Takeuchi, Jean‐Marc Reichhart, and Nicolas Matt. Akirin specifies nf-κb selectivity of drosophila innate immune response via chromatin remodeling. The EMBO Journal, 33:2349-2362, Sep 2014. URL: https://doi.org/10.15252/embj.201488456, doi:10.15252/embj.201488456. This article has 124 citations.
(tartey2016akirin2mediatedtranscriptionalcontrol pages 8-10): Sarang Tartey and Osamu Takeuchi. Akirin2-mediated transcriptional control by recruiting swi/snf complex in b cells. Critical reviews in immunology, 36 5:395-406, Jan 2016. URL: https://doi.org/10.1615/critrevimmunol.2017019629, doi:10.1615/critrevimmunol.2017019629. This article has 8 citations and is from a peer-reviewed journal.
(karabay2018expressionanalysisof pages 7-7): Arzu Zeynep Karabay, Asli Koc, Tulin Ozkan, Yalda Hekmatshoar, Buket Altinok Gunes, Asuman Sunguroglu, Zeliha Buyukbingol, Arzu Atalay, and Fugen Aktan. Expression analysis of akirin-2, nfκb-p65 and β-catenin proteins in imatinib resistance of chronic myeloid leukemia. Hematology, 23:765-770, Jun 2018. URL: https://doi.org/10.1080/10245332.2018.1488795, doi:10.1080/10245332.2018.1488795. This article has 21 citations and is from a peer-reviewed journal.
(burton2024functionalizingtandemmass pages 5-7): Nikolas R. Burton and Keriann M. Backus. Functionalizing tandem mass tags for streamlining click-based quantitative chemoproteomics. Communications Chemistry, Apr 2024. URL: https://doi.org/10.1038/s42004-024-01162-x, doi:10.1038/s42004-024-01162-x. This article has 17 citations and is from a peer-reviewed journal.
(burton2024functionalizingtandemmass media b5b8243d): Nikolas R. Burton and Keriann M. Backus. Functionalizing tandem mass tags for streamlining click-based quantitative chemoproteomics. Communications Chemistry, Apr 2024. URL: https://doi.org/10.1038/s42004-024-01162-x, doi:10.1038/s42004-024-01162-x. This article has 17 citations and is from a peer-reviewed journal.
(burton2024functionalizingtandemmass media 0c97aa47): Nikolas R. Burton and Keriann M. Backus. Functionalizing tandem mass tags for streamlining click-based quantitative chemoproteomics. Communications Chemistry, Apr 2024. URL: https://doi.org/10.1038/s42004-024-01162-x, doi:10.1038/s42004-024-01162-x. This article has 17 citations and is from a peer-reviewed journal.
(luo2024acorenrf2 pages 4-7): George Luo, Harshita Kumar, Kristin Aldridge, Stevie Rieger, EunHyang Han, Ethan Jiang, Ernest R. Chan, Ahmed Soliman, Haider Mahdi, and John J. Letterio. A core nrf2 gene set defined through comprehensive transcriptomic analysis predicts selective drug resistance and poor multicancer prognosis. Dec 2024. URL: https://doi.org/10.1089/ars.2023.0409, doi:10.1089/ars.2023.0409. This article has 13 citations and is from a domain leading peer-reviewed journal.
(yamazaki2024thenuclearnfκb pages 4-6): Soh Yamazaki. The nuclear nf-κb regulator iκbζ: updates on its molecular functions and pathophysiological roles. Cells, 13:1467, Aug 2024. URL: https://doi.org/10.3390/cells13171467, doi:10.3390/cells13171467. This article has 19 citations.
(jin2024theroleof pages 5-6): Juan Jin, Qinqin Guo, and Zhibin Yan. The role of lutheran/basal cell adhesion molecule in hematological diseases and tumors. International Journal of Molecular Sciences, 25:7268, Jul 2024. URL: https://doi.org/10.3390/ijms25137268, doi:10.3390/ijms25137268. This article has 6 citations.
(jin2024theroleof pages 8-10): Juan Jin, Qinqin Guo, and Zhibin Yan. The role of lutheran/basal cell adhesion molecule in hematological diseases and tumors. International Journal of Molecular Sciences, 25:7268, Jul 2024. URL: https://doi.org/10.3390/ijms25137268, doi:10.3390/ijms25137268. This article has 6 citations.

Artifacts

Edison artifact artifact-00

Citations

karabay2018expressionanalysisof pages 7-7
burton2024functionalizingtandemmass pages 5-7
jin2024theroleof pages 5-6
jin2024theroleof pages 8-10
https://doi.org/10.1038/s42004-024-01162-x
https://doi.org/10.1089/ars.2023.0409
https://doi.org/10.3390/cells13171467
https://doi.org/10.1615/critrevimmunol.2017019629
https://doi.org/10.15252/embj.201488456
https://doi.org/10.1615/CritRevImmunol.2017019629
https://doi.org/10.3390/ijms25137268
https://doi.org/10.1080/10245332.2018.1488795
https://doi.org/10.1615/critrevimmunol.2017019629,
https://doi.org/10.15252/embj.201488456,
https://doi.org/10.1080/10245332.2018.1488795,
https://doi.org/10.1038/s42004-024-01162-x,
https://doi.org/10.1089/ars.2023.0409,
https://doi.org/10.3390/cells13171467,
https://doi.org/10.3390/ijms25137268,

📚 Additional Documentation

Notes

(AKIRIN2-notes.md)

AKIRIN2 PN Review Notes

Deep research status

Falcon deep research was attempted with perplexity-lite fallback for the PN review. Falcon timed out after 600 seconds, and the fallback provider returned a quota/401 error, so no provider-authored AKIRIN2-deep-research-*.md file was available for this review. The review below uses cached GOA, UniProt, PN projection, and publication files instead.

Proteostasis projection

The PN projection has one AKIRIN2 candidate addition: GO:0070628 proteasome binding, from Ubiquitin Proteasome System|Proteasome and associated proteins|adaptors|Akirin in projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv.

This projection is supported by direct primary evidence, not merely by the PN bucket. The AKIRIN2 proteasome-import paper reports that AKIRIN2 is required for nuclear protein degradation and that AKIRIN2 homodimers "directly bind to fully assembled 20S proteasomes" to mediate nuclear import PMID:34711951. UniProt summarizes the same mechanism as AKIRIN2 binding 20S proteasomes at one end and IPO9 at the other to import pre-assembled proteasomes through the nuclear pore [file:human/AKIRIN2/AKIRIN2-uniprot.txt "directly binds to fully assembled 20S proteasomes at one end and to nuclear import receptor IPO9 at the other end"].

Decision: add GO:0070628 proteasome binding as a NEW annotation with PMID:34711951, and modify the generic protein binding annotation from the same paper toward proteasome binding plus protein-macromolecule adaptor activity.

Existing GOA review stance

AKIRIN2's core PN function is proteasome binding/adaptor-mediated nuclear proteasome import, directly involved in protein import into nucleus, proteasome localization, and nuclear protein quality control by the ubiquitin-proteasome system [PMID:34711951 "nuclear import of proteasomes in vertebrates"; PMID:34711951 "nuclear protein degradation"].

The conserved transcriptional coregulator role is also real. The original akirin paper shows human AKIRIN2 is nuclear PMID:18066067 and that mouse Akirin2 acts downstream of NF-kappaB for TLR/IL-1R-inducible gene expression PMID:18066067. These transcription and immune annotations are valid, but in the PN batch they should not be used to broaden AKIRIN2 beyond the supported proteasome-import projection.

The high-throughput interactome protein binding and enzyme binding annotations do not establish a specific AKIRIN2 activity. They were marked as over-annotated unless rescued by more specific mechanistic evidence. The exception is identical protein binding, because the proteasome-import paper independently reports AKIRIN2 homodimer formation PMID:34711951.

Open question

The main biology still unclear for curation is whether AKIRIN2's NF-kappaB/chromatin co-regulator complexes are mechanistically coupled to, or separable from, its proteasome-import adapter function.

Falcon deep research findings (2026-06-07)

A Falcon (Edison Scientific) deep research report was generated for AKIRIN2; the earlier note above (Falcon timed out) is now superseded for the transcription/immune arm. The report's mechanistic core overlaps with the existing review (nuclear adaptor; NF-kappaB-dependent transcription; SWI/SNF), but it adds named primary references and mechanistic specifics that were previously only implied via the UniProt summary. PMIDs below were resolved/confirmed via PubMed (search + metadata).

CONFIRMS / NEW reference: AKIRIN2 acts as a molecular bridge linking NF-kappaB output to SWI/SNF (BAF/BRG1) chromatin remodelers, conferring selective (not global) induction of a subset of NF-kappaB target genes; Akirin-dependent promoters are enriched for lower CpG-island density. The conserved "molecular selector" mechanism (Akirin connecting Relish to the Osa/BAP60 SWI/SNF-like BAP complex; required for a subset of Relish-dependent effector genes, dispensable for negative-regulator genes) is from Drosophila but described as conserved to mammals [PMID:25180232 Bonnay et al. 2014 EMBO J "Akirins act as molecular selectors specifying the choice between subsets of NF-kappaB target genes"]. The mammalian B-cell/macrophage synthesis is reviewed in [PMID:28605346 Tartey & Takeuchi 2016 Crit Rev Immunol]. This adds primary-literature grounding for the existing GO:0003712 transcription coregulator activity and GO:0045944 annotations, which previously rested mainly on PMID:18066067.
NEW reference (B-cell mechanism): Mouse Akirin2 is required for BRG1 (SWI/SNF) recruitment to Myc and Ccnd2 promoters after mitogenic (CD40/TLR/BCR) stimulation, supporting B-cell proliferation, survival, and T-dependent/independent humoral responses; Akirin2-deficient B cells show impaired cyclin D/c-Myc expression [PMID:26041538 Tartey et al. 2015 J Immunol "Brg1 recruitment to the Myc and Ccnd2 promoter was severely impaired in Akirin2-deficient B cells"]. This is the experimental primary support for the existing GO:0050871 positive regulation of B cell activation and GO:0002821 adaptive-immune annotations (previously IEA/ISS-only with PMID:18066067 as indirect support).
NEW (disease link, provisional/association): Increased nuclear accumulation of Akirin-2 was reported in imatinib-resistant chronic myeloid leukemia (K562) cells, proposed as a candidate biomarker; notably the same study found NO direct NFkB-p65/Akirin-2 co-IP interaction in that system [PMID:29945498 Karabay et al. 2018 Hematology "increased Akirin-2 protein accumulation in the nucleus was shown for the first time in imatinib resistant CML cells"]. Association-level; not used to change any annotation.
PROVISIONAL / not used for annotation: A 2024 chemoproteomics study lists AKIRIN2 Cys3 as a uniquely ligandable cysteine proximal to a 20S-proteasome-binding motif (Burton & Backus 2024, Commun Chem, doi:10.1038/s42004-024-01162-x). This is chemical-tractability data, not a function; consistent with the established proteasome-binding adaptor role but adds no GO annotation. Kept in notes only.
PROVISIONAL / not used for annotation: A 2024 NRF2 transcriptomic meta-analysis reports AKIRIN2 as a conditional NRF2-responsive transcript (induced mainly under pharmacologic NRF2 activation, inconsistent across cancer cohorts) (Luo et al. 2024, Antioxid Redox Signal, doi:10.1089/ars.2023.0409). Expression-association only; does not establish direct NRF2 regulation of AKIRIN2. Kept in notes only.

Curation impact: The transcription/immune arm of the review is enriched with four genuine primary references (PMID:25180232, PMID:28605346, PMID:26041538, PMID:29945498) added as validation-safe statement-only entries. No proteasome-import (PN core) annotations are changed; the Falcon material is integrated as additional support for the already-present transcription-coregulator and immune-output annotations rather than as new GO terms. No annotation action values were altered.

Pn Notes

(AKIRIN2-pn-notes.md)

AKIRIN2 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q53H80
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-03 (PR 1361)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/AKIRIN2/AKIRIN2-ai-review.yaml
AIGR review HTML: present - genes/human/AKIRIN2/AKIRIN2-ai-review.html
Gene notes: present - genes/human/AKIRIN2/AKIRIN2-notes.md
GOA TSV: present - genes/human/AKIRIN2/AKIRIN2-goa.tsv
UniProt record: present - genes/human/AKIRIN2/AKIRIN2-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/AKIRIN2.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/AKIRIN2.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/AKIRIN2/AKIRIN2-deep-research-falcon.md

AIGR Review Snapshot

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/core annotation action counts: ACCEPT: 16; KEEP_AS_NON_CORE: 17; MARK_AS_OVER_ANNOTATED: 9; MODIFY: 1; NEW: 1

PN Consistency Summary

Consistency: Fully consistent across all four layers. Deep research (falcon), review, PN annotation, and PN-node mapping all agree AKIRIN2 is the proteasome-import adaptor: homodimers bridge assembled 20S proteasomes to importin IPO9 for nuclear import (PMID:34711951). Review adopts the PN projection as action NEW GO:0070628, plus GO:0030674 adaptor activity, GO:0006606, GO:0031144, GO:0071630 — a coherent proteostasis core.
PN story / NEW pressure: PN asserts proteasome binding not in GOA; GOA confirms only GO:0031144 and GO:0071630 are present (GO:0070628 genuinely new_to_goa). GO:0070628 verified real and directly supported by primary biochemistry. Verdict: ADD — well justified; this is the model case the Akirin bucket was built for.
Evidence alignment: Strong overlap. PN reference 34711951 = the central review reference PMID:34711951. Review additionally MARK_AS_OVER_ANNOTATED the many high-throughput protein-binding rows (PMID:16189514, 28514442, 31515488, 32296183, 33961781, 40205054) — consistent triage, no conflict.
Verdict: Consistent and well-supported; GO:0070628 ADD confirmed (already realized as NEW in review).

Full Consistency Review

UniProt: Q53H80 · batch: proteostasis-batch-2026-06-03 · review status: COMPLETE
PN placement: Ubiquitin Proteasome System|Proteasome and associated proteins|adaptors|Akirin ; PN-node mapping: Akirin type no_mapping; group (adaptors) mapped→GO:0070628 (proteasome binding, propagate); class context_only→GO:0000502. Projection: GO:0070628 new_to_goa.
Consistency: Fully consistent across all four layers. Deep research (falcon), review, PN annotation, and PN-node mapping all agree AKIRIN2 is the proteasome-import adaptor: homodimers bridge assembled 20S proteasomes to importin IPO9 for nuclear import (PMID:34711951). Review adopts the PN projection as action NEW GO:0070628, plus GO:0030674 adaptor activity, GO:0006606, GO:0031144, GO:0071630 — a coherent proteostasis core.
PN story / NEW pressure: PN asserts proteasome binding not in GOA; GOA confirms only GO:0031144 and GO:0071630 are present (GO:0070628 genuinely new_to_goa). GO:0070628 verified real and directly supported by primary biochemistry. Verdict: ADD — well justified; this is the model case the Akirin bucket was built for.
Mapping strategy: No change to the node for AKIRIN2; the adaptors→GO:0070628 mapping is exactly right here. (The only caveat is shared with AKIRIN1: the Akirin type lumps both paralogs, and the proteasome activity is AKIRIN2-specific — see AKIRIN1 recommendation to split. AKIRIN2 keeps the mapping.) PN-projected GO:0070628 is appropriately specific (neither broader nor narrower than the review's core MF).
Evidence alignment: Strong overlap. PN reference 34711951 = the central review reference PMID:34711951. Review additionally MARK_AS_OVER_ANNOTATED the many high-throughput protein-binding rows (PMID:16189514, 28514442, 31515488, 32296183, 33961781, 40205054) — consistent triage, no conflict.
Verdict: Consistent and well-supported; GO:0070628 ADD confirmed (already realized as NEW in review).
Recommended edits: None for AKIRIN2 (mapping and review aligned). (Cross-ref: the AKIRIN1 split recommendation keeps GO:0070628 on AKIRIN2 only.)

PN Dossier Context

review_batch: proteostasis-batch-2026-06-03
review_yaml: genes/human/AKIRIN2/AKIRIN2-ai-review.yaml
PN workbook rows: 1

PN row 1: Ubiquitin Proteasome System | Proteasome and associated proteins | adaptors | Akirin

UniProt: Q53H80
In branches: UPS
Signature domains: IPR024132
Auxiliary domains: (none)
PN references (titles):
- 34711951
PN-node mapping records (path + ancestors):
- [type] Ubiquitin Proteasome System|Proteasome and associated proteins|adaptors|Akirin
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower proteasome component, chaperone, adaptor, domain, or isoform subdivision already covered by a curated parent proteasome mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|Proteasome and associated proteins|adaptors
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0070628 proteasome binding]
  rationale: This PN group captures proteasome adaptors and shuttle factors. Proteasome binding is the safe shared molecular-function target.
- [class] Ubiquitin Proteasome System|Proteasome and associated proteins
  status=context_only scope=too_broad_to_propagate GO=[GO:0000502 proteasome complex]
  rationale: This class records the proteasome branch context, but descendants include core and regulatory particle subunits, activators, assembly chaperones, adaptors, DUBs, E3 ligases, enzymes, and transcriptional regulators. Propagation should come from narrower nodes.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (1)

GO:0070628 proteasome binding | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|Proteasome and associated proteins|adaptors

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

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

AKIRIN2

Gene Description

Existing Annotations Review

Core Functions

Proteasome-binding adaptor role that imports assembled proteasomes into the nucleus to maintain nuclear proteasome-dependent protein degradation.

Nuclear transcription-coregulator/adaptor role for inducible gene expression downstream of NF-kappaB and chromatin-remodeling machinery.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research report: Human AKIRIN2 (Akirin-2; UniProt Q53H80, gene symbol AKIRIN2; synonym C6orf166) — functional annotation

0) Mandatory identity verification (disambiguation)

1) Key concepts and definitions (current understanding)

1.1 What AKIRIN2 is (functional class)

1.2 “NF-κB selectivity” and “chromatin remodeling bridge”

1.3 Protein features relevant to function

2) Experimentally supported functions, pathways, partners, and localization

2.1 Core molecular function: adaptor linking NF-κB/IκBζ to SWI/SNF (BAF)

2.2 Immune-cell biology: B cell activation programs

2.3 Developmental essentiality (strong genetic evidence from mouse)

2.4 Promoter-context selectivity (epigenetic logic)

2.5 Subcellular localization

3) Recent developments (prioritizing 2023–2024)

3.1 2024 chemoproteomics: a newly observed ligandable cysteine in AKIRIN2

3.2 2024 transcriptional meta-analysis: AKIRIN2 as a conditional NRF2-responsive gene

3.3 2023–2024 updates on the IκBζ axis (contextual, not AKIRIN2-specific in retrieved excerpt)

4) Current applications and real-world implementations

4.1 Translational relevance: cancer-associated expression and resistance phenotypes

4.2 Chemical biology opportunity: ligandability at Cys3

4.3 Systems biology signatures: NRF2 activation scoring

5) Expert opinions / authoritative synthesis

6) Relevant statistics and quantitative findings (from retrieved recent and foundational studies)

Consolidated evidence table

Conclusion (functional annotation summary)

Artifacts

Citations

📚 Additional Documentation

Notes

AKIRIN2 PN Review Notes

Deep research status

Proteostasis projection

Existing GOA review stance

Open question

Falcon deep research findings (2026-06-07)

Pn Notes

AKIRIN2 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Ubiquitin Proteasome System | Proteasome and associated proteins | adaptors | Akirin

Projected GO annotations (1)

Note

📄 View Raw YAML