Affinage

AKIRIN2

Akirin-2 · UniProt Q53H80

Length
203 aa
Mass
22.5 kDa
Annotated
2026-06-09
36 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AKIRIN2 is a conserved nuclear protein that functions dually as an importin-coupled adaptor for proteasome nuclear import and as a transcriptional scaffold bridging signaling to chromatin remodeling (PMID:34711951, PMID:25107474). As a homodimer, it binds directly to fully assembled 20S proteasomes and is required for their nuclear import; cells lacking AKIRIN2 lose nuclear proteasomes and accumulate nuclear substrates such as MYC, and during mitosis AKIRIN2 re-imports proteasomes into newly formed daughter nuclei (PMID:34711951). Mechanistically, a wing helix within a disordered region stabilizes the proteasome interaction, and AKIRIN2 homodimers nucleate stepwise recruitment of importins (including IPO9) into a multivalent cluster that amplifies nuclear localization signals for efficient translocation, after which RanGTP releases the importins and AKIRIN2 is degraded by the proteasome in a ubiquitin-independent manner [PMID:bio_10.1101_2024.11.08.622636]. In its transcriptional role, AKIRIN2 links the NF-κB pathway to the SWI/SNF complex by interacting with BAF60 proteins and with IκB-ζ (in complex with NF-κB p50), an interaction required for induction of proinflammatory genes such as Il6 and Il12b in macrophages and for Brg1 recruitment to Myc and Ccnd2 promoters driving B cell proliferation (PMID:25107474, PMID:26041538). Consistent with a chromatin-remodeling role acting upstream of progenitor maintenance and cell-survival programs, AKIRIN2 is required across development for cortical progenitor survival, neural progenitor maintenance, myogenesis, and interdigital cell death, acting via BAF complexes and modulating outputs including p53, Wnt3a, and Fgf8 (PMID:27871306, PMID:28193841, PMID:35198879, PMID:30801883, PMID:30116001).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2013 Medium

    Established an early functional handle on Akirin2 as a transcriptional repressor in cancer, showing it associates with a partner to control a specific target promoter.

    Evidence Reporter assays, ChIP, and antisense knockdown defining an FBI1/Akirin2–14-3-3β complex repressing the BCAM promoter in tumor cells

    PMID:24223164

    Open questions at the time
    • Direct mechanism of repression at chromatin not resolved
    • Generality beyond BCAM/tumor context untested
  2. 2014 High

    Answered how Akirin2 connects inflammatory signaling to gene activation by identifying it as the physical bridge between NF-κB-associated IκB-ζ and the SWI/SNF remodeler.

    Evidence Reciprocal Co-IP, ChIP, macrophage-specific knockout, and infection/reporter models showing an IκB-ζ–Akirin2–BAF60 complex required for Il6/Il12b induction

    PMID:25107474

    Open questions at the time
    • Structural basis of BAF60 and IκB-ζ binding unknown
    • Which BAF60 paralog(s) are engaged not fully resolved
  3. 2015 High

    Extended the SWI/SNF scaffolding role to cell-cycle control, showing Akirin2 is needed for Brg1 recruitment to proliferation-gene promoters.

    Evidence B cell-specific conditional knockout with promoter-level ChIP and in vivo immunization readouts linking Akirin2 to cyclin D/c-Myc expression

    PMID:26041538

    Open questions at the time
    • Whether Akirin2 directly recruits Brg1 or acts indirectly not distinguished
    • Connection to its proteasome-import role not addressed
  4. 2016 Medium

    Demonstrated an essential developmental requirement for Akirin2 in progenitor survival, broadening its role beyond immunity.

    Evidence Emx1-Cre conditional knockout with EdU labeling and in situ hybridization showing massive apoptosis and defective Wnt3a/cortical hem formation

    PMID:27871306

    Open questions at the time
    • Molecular target linking Akirin2 to Wnt3a not identified
    • Whether the phenotype reflects chromatin or proteasome function unknown
  5. 2017 Medium

    Placed Akirin2 epistatically within neural and muscle differentiation programs, linking it to BAF complexes and to ERK/NFAT/calcineurin signaling.

    Evidence Xenopus knockdown/epistasis with a BAF53a-containing complex (Sox2/N-tubulin), and porcine satellite-cell overexpression/siRNA with pathway readouts (ERK1/2, NFATc1, calcineurin)

    PMID:28193841 PMID:28223540 PMID:28327665

    Open questions at the time
    • Direct binding to BAF53a-complex not shown in these studies
    • Signaling links (ERK/NFAT) inferred from pathway readouts, not biochemistry
  6. 2019 Medium

    Confirmed an in vivo requirement for Akirin2 in mammalian myogenesis through progenitor survival and differentiation marker expression.

    Evidence Sim1-Cre conditional knockout causing neonatal lethality, muscle agenesis from Pax3+ myoblast apoptosis, and impaired myogenin/MyHC expression in vitro

    PMID:30801883

    Open questions at the time
    • Molecular partners mediating myogenic gene control not defined
    • Cause of myoblast apoptosis not mechanistically linked to a target
  7. 2021 High

    Resolved a distinct, non-transcriptional core function: AKIRIN2 mediates nuclear import of assembled proteasomes, defining a mechanism for nuclear protein homeostasis.

    Evidence CRISPR screen, Co-IP, intracellular immunostaining, FACS, and live imaging showing homodimeric AKIRIN2 binds 20S proteasomes and re-imports them into daughter nuclei after mitosis

    PMID:34711951

    Open questions at the time
    • Importin identity and assembly mechanism not yet defined
    • Relationship to the SWI/SNF scaffolding role unresolved
  8. 2022 Medium

    Connected loss of nuclear AKIRIN2 function to a cell-survival pathway, placing it upstream of p53-driven death in mature neurons.

    Evidence Neuron-specific conditional knockout with transcriptomics and Trp53-reduction genetic rescue of necroptotic neurodegeneration

    PMID:35198879

    Open questions at the time
    • Whether p53 upregulation reflects loss of proteasome import is not directly tested
    • Mechanistic link between AKIRIN2 loss and necroptosis incomplete
  9. 2024 High

    Provided the structural and mechanistic basis for proteasome import, showing AKIRIN2 is a multivalent importin-clustering adaptor that is degraded after delivery.

    Evidence Saturation mutagenesis screens, cryo-EM, and biochemical reconstitution defining a wing helix-stabilized interaction, stepwise IPO9/importin recruitment, RanGTP release, and ubiquitin-independent degradation (preprint)

    PMID:bio_10.1101_2024.11.08.622636

    Open questions at the time
    • Peer review pending
    • How the import function is coordinated with transcriptional roles unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how AKIRIN2's two functions — proteasome nuclear import and SWI/SNF transcriptional scaffolding — are mechanistically integrated within a single cell and across its many developmental contexts.
  • No study tests whether developmental phenotypes arise from loss of proteasome import vs. chromatin remodeling
  • Structural basis of BAF60/IκB-ζ binding undefined
  • Regulation switching between the two functions unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 3
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-168256 Immune System 2 R-HSA-4839726 Chromatin organization 2 R-HSA-9609507 Protein localization 2
Partners
BAF60IPO9NFKB1NFKBIZYWHAB
Complex memberships
20S proteasome (transient import complex)SWI/SNF chromatin remodeling complex

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 AKIRIN2 forms homodimers that directly bind to fully assembled 20S proteasomes and mediates their nuclear import in vertebrates. During mitosis, proteasomes are excluded from condensing chromatin and re-imported into newly formed daughter nuclei in an AKIRIN2-dependent process. Cells lacking AKIRIN2 become devoid of nuclear proteasomes, causing accumulation of MYC and other nuclear proteins. CRISPR screen, Co-IP, intracellular immunostaining, FACS, live cell imaging, biochemical fractionation Nature High 34711951
2024 AKIRIN2 acts as a scaffold/adaptor protein that coordinates stepwise assembly of an importin cluster around the proteasome. A wing helix in a disordered region of AKIRIN2 stabilizes proteasome interactions. AKIRIN2 homodimers recruit importin IPO9, which facilitates binding of a second AKIRIN2 homodimer that recruits additional importins, creating a multivalent assembly that amplifies nuclear localization signals for efficient proteasome translocation. Inside the nucleus, RanGTP dissociates importins, and AKIRIN2 is degraded by the proteasome in a ubiquitin-independent manner. Protein-wide saturation mutagenesis screens (FACS- and microscopy-based), cryo-EM, biochemical reconstitution bioRxivpreprint High bio_10.1101_2024.11.08.622636
2014 Akirin2 bridges the NF-κB pathway and the SWI/SNF chromatin remodeling complex by interacting with BAF60 proteins and IκB-ζ (which forms a complex with NF-κB p50). This IκB-ζ–Akirin2–BAF60 complex is essential for TLR-, RIG-I-, and Listeria-mediated induction of proinflammatory genes (Il6, Il12b) in macrophages. Akirin2 and IκB-ζ mutually depend on each other for recruitment to the Il6 promoter. Co-immunoprecipitation, chromatin immunoprecipitation, macrophage-specific knockout, reporter assays, infection models The EMBO journal High 25107474
2015 Akirin2 is required for B cell cycle progression and humoral immune responses by controlling the SWI/SNF complex. Akirin2-deficient B cells show defective expression of cyclin D and c-Myc, and impaired Brg1 recruitment to Myc and Ccnd2 promoters. B cell-specific knockout leads to decreased follicular and peritoneal B-1 cell numbers, defective proliferation, and apoptosis in response to TLR ligands, CD40, and BCR stimulation. B cell-specific conditional knockout (Cd19-Cre), chromatin immunoprecipitation, flow cytometry, in vivo immunization Journal of immunology High 26041538
2013 FBI1/Akirin2 forms a complex with 14-3-3β that acts as a transcriptional repressor binding to the BCAM promoter, suppressing BCAM expression and thereby promoting tumorigenicity and metastasis. Luciferase reporter assay, chromatin immunoprecipitation, antisense knockdown, in vivo tumor assay PloS one Medium 24223164
2017 Akirin2 regulates proliferation and differentiation of porcine skeletal muscle satellite cells through ERK1/2 and NFATc1 signaling pathways, as demonstrated by overexpression and siRNA knockdown experiments. Overexpression and siRNA knockdown, western blot, cell proliferation/differentiation assays Scientific reports Medium 28327665
2016 Akirin2 is required for early cortical progenitor survival and proliferation during cerebral cortex formation. Loss of Akirin2 in cortical progenitors causes massive apoptosis starting at E10, failure of normal proliferation, and defective Wnt3a signaling/cortical hem formation. Cortex-restricted conditional knockout (Emx1-Cre), EdU labeling, in situ hybridization, immunohistochemistry Neural development Medium 27871306
2017 Akirin2 in Xenopus neural development acts upstream of BAF53a-containing BAF complex to maintain neural progenitor state (regulating Sox2 expression antagonistically to Geminin), and also acts upstream of NeuroD and in parallel with Ngnr1 for terminal neuronal differentiation (regulating N-tubulin expression). Xenopus knockdown, epistasis analysis, rescue experiments, in situ hybridization The Journal of biological chemistry Medium 28193841
2022 Akirin2 loss in mature cortical neurons causes progressive neurodegeneration via necroptosis, associated with upregulation of p53 (Trp53) target genes. Genetic reduction of Trp53 rescued neurodegeneration in Akirin2-null neurons, placing Akirin2 upstream of p53-mediated cell death pathways. Neuron-specific conditional knockout, transcriptomics, genetic epistasis (Trp53 reduction rescue), histology iScience Medium 35198879
2019 Akirin2 is required for mammalian myogenesis in vivo; loss in somitic muscle precursors via Sim1-Cre leads to neonatal lethality, absence of forelimb/intercostal/diaphragm muscles due to apoptosis of Pax3-positive myoblasts, and impaired expression of myogenin and myosin heavy chain during muscle cell differentiation in vitro. Conditional knockout (Sim1-Cre), immunohistochemistry, in vitro differentiation assays, western blot Genesis Medium 30801883
2018 Akirin2 is required for interdigital tissue regression in the mouse limb; knockout in limb epithelium leads to loss of interdigital cell death, increased cell proliferation, and soft-tissue syndactyly. This is associated with perdurance of Fgf8 expression, implicating Akirin2 in downregulation of Fgf8 from the apical ectodermal ridge. Conditional knockout in limb epithelium, immunohistochemistry, in situ hybridization Scientific reports Medium 30116001
2017 Akirin2 promotes slow MyHC I expression via calcineurin (CaN)/NFATc1 signaling pathway in porcine skeletal muscle satellite cells; knockdown of Akirin2 decreases CaN activity and NFATc1 expression, while overexpression has the opposite effect, and inhibition of CaN or NFATc1 knockdown blocks Akirin2 overexpression-induced upregulation of MyHC I. siRNA knockdown, overexpression, pharmacological inhibition, western blot, qPCR Oncotarget Medium 28223540
2016 Duck Akirin2 promotes myoblast proliferation (but not differentiation) via activation of the mTOR/p70S6K signaling pathway; rapamycin blocks Akirin2-induced increases in cell viability, mTOR and p70S6K mRNA, and phospho-mTOR/phospho-p70S6K protein levels. Overexpression, pharmacological inhibition (rapamycin), flow cytometry, western blot The international journal of biochemistry & cell biology Low 27590857
2024 AjAkirin2 (sea cucumber ortholog) directly interacts with Aj14-3-3ζ as demonstrated by GST-pulldown and co-IP assays. AjAkirin2 positively regulates Aj14-3-3ζ expression, and knockdown of either protein increases intracellular bacterial load and suppresses NF-κB signaling pathway genes and inflammatory cytokines. GST-pulldown, co-immunoprecipitation, RNAi knockdown, bacterial load assay, qPCR Fish & shellfish immunology Medium 38685443
2019 Akirin2 induces angiogenesis in cholangiocarcinoma by increasing VEGFA expression through activation of the IL-6/STAT3 signaling pathway, and promotes EMT-associated migration and invasion. miR-490-3p negatively regulates Akirin2 expression at the post-transcriptional level via its 3'-UTR. Lentiviral knockdown/overexpression, luciferase reporter assay (3'-UTR), in vivo tumor model, western blot Cell death & disease Low 30886152
2014 FBI1/Akirin2 downregulation in Lewis lung carcinoma cells decreased anchorage-independent growth and reduced tumor growth and metastasis in vivo, indicating FBI1/Akirin2 overexpression is required for LLC1 tumor growth and metastasis. Antisense knockdown, in vitro anchorage-independent growth assay, in vivo nude mouse tumor assay Biochemical and biophysical research communications Low 24468084

Source papers

Stage 0 corpus · 36 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 AKIRIN2 controls the nuclear import of proteasomes in vertebrates. Nature 93 34711951
2014 Akirin2 is critical for inducing inflammatory genes by bridging IκB-ζ and the SWI/SNF complex. The EMBO journal 87 25107474
2019 Akirin2 is modulated by miR-490-3p and facilitates angiogenesis in cholangiocarcinoma through the IL-6/STAT3/VEGFA signaling pathway. Cell death & disease 38 30886152
2015 Chromatin Remodeling and Transcriptional Control in Innate Immunity: Emergence of Akirin2 as a Novel Player. Biomolecules 32 26287257
2015 Essential Function for the Nuclear Protein Akirin2 in B Cell Activation and Humoral Immune Responses. Journal of immunology (Baltimore, Md. : 1950) 31 26041538
2017 Akirin2 regulates proliferation and differentiation of porcine skeletal muscle satellite cells via ERK1/2 and NFATc1 signaling pathways. Scientific reports 23 28327665
2013 The FBI1/Akirin2 target gene, BCAM, acts as a suppressive oncogene. PloS one 22 24223164
2016 Akirin2 is essential for the formation of the cerebral cortex. Neural development 17 27871306
2015 Down regulation of Akirin-2 increases chemosensitivity in human glioblastomas more efficiently than Twist-1. Oncotarget 16 26036627
2014 FBI1/Akirin2 promotes tumorigenicity and metastasis of Lewis lung carcinoma cells. Biochemical and biophysical research communications 16 24468084
2012 Molecular cloning, tissue distribution, and functional analysis of porcine Akirin2. Animal biotechnology 16 22537061
2018 Arginine Promotes Slow Myosin Heavy Chain Expression via Akirin2 and the AMP-Activated Protein Kinase Signaling Pathway in Porcine Skeletal Muscle Satellite Cells. Journal of agricultural and food chemistry 15 29685038
2017 Dual roles of Akirin2 protein during Xenopus neural development. The Journal of biological chemistry 15 28193841
2014 The identification of the first molluscan Akirin2 with immune defense function in the Hong Kong oyster Crassostrea hongkongensis. Fish & shellfish immunology 15 25284180
2018 Expression analysis of Akirin-2, NFκB-p65 and β-catenin proteins in imatinib resistance of chronic myeloid leukemia. Hematology (Amsterdam, Netherlands) 14 29945498
2014 Identification and molecular characterization of an Akirin2 homolog in Chinese loach (Paramisgurnus dabryanus). Fish & shellfish immunology 14 24389387
2018 An essential role for the nuclear protein Akirin2 in mouse limb interdigital tissue regression. Scientific reports 12 30116001
2011 Distribution of allele frequencies at TTN g.231054C > T, RPL27A g.3109537C > T and AKIRIN2 c.*188G > A between Japanese Black and four other cattle breeds with differing historical selection for marbling. BMC research notes 12 21251324
2013 Akirin2 homologues from rock bream, Oplegnathus fasciatus: Genomic and molecular characterization and transcriptional expression analysis. Fish & shellfish immunology 11 23770624
2020 Transcription profile, NF-ĸB promoter activation, and antiviral activity of Amphiprion clarkii Akirin-2. Fish & shellfish immunology 10 33259930
2015 Effect of porcine Akirin2 on skeletal myosin heavy chain isoform expression. International journal of molecular sciences 9 25686036
2014 Molecular cloning, sequence analysis and tissue-specific expression of Akirin2 gene in Tianfu goat. Gene 9 25239665
2016 Akirin2 could promote the proliferation but not the differentiation of duck myoblasts via the activation of the mTOR/p70S6K signaling pathway. The international journal of biochemistry & cell biology 8 27590857
2022 p53-mediated neurodegeneration in the absence of the nuclear protein Akirin2. iScience 7 35198879
2019 A critical role for the nuclear protein Akirin2 in the formation of mammalian muscle in vivo. Genesis (New York, N.Y. : 2000) 7 30801883
2017 Effects of Active Immunization Against Akirin2 on Muscle Fiber-type Composition in Pigs. Animal biotechnology 7 29144179
2011 Molecular cloning, sequence characterization, and tissue expression analysis of Hi-Line Brown chicken Akirin2. The protein journal 6 21858694
2024 Transcranial direct current stimulation enhances the protective effect of isoflurane preconditioning on cerebral ischemia/reperfusion injury: A new mechanism associated with the nuclear protein Akirin2. CNS neuroscience & therapeutics 5 39267282
2017 Akirin2 promotes slow myosin heavy chain expression by CaN/NFATc1 signaling in porcine skeletal muscle satellite cells. Oncotarget 5 28223540
2022 Nuclear destruction: A suicide mission by AKIRIN2 brings intact proteasomes into the nucleus. Molecular cell 4 34995507
2015 Akirin2 expression in response to vaccine-induced immunity in chicken. Genetics and molecular research : GMR 4 26782392
2024 Akirin2 enhances antibacterial ability via interacting with 14-3-3ζ in V. splendidus-challenged Apostichopus japonicus. Fish & shellfish immunology 3 38685443
2016 Akirin2-Mediated Transcriptional Control by Recruiting SWI/SNF Complex in B Cells. Critical reviews in immunology 3 28605346
2014 Cloning and expression pattern of akirin2 gene in broiler. Molecular and cellular biochemistry 3 25098451
2020 Distribution of the variant at AKIRIN2: c.*188G > A in Chinese cattle. Animal biotechnology 1 32779549
2025 Akirin2 regulates IL-6 expression and contributes to immune defense in silver pomfret (Pampus argenteus). Fish & shellfish immunology 0 41192674

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