Affinage

AKIRIN2

Akirin-2 · UniProt Q53H80

Length
203 aa
Mass
22.5 kDa
Annotated
2026-04-28
36 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AKIRIN2 is a conserved nuclear scaffold protein that operates at the intersection of proteasome homeostasis and chromatin-dependent transcriptional regulation. It forms homodimers that bind fully assembled 20S proteasomes and recruit importin IPO9 through a wing-helix motif, driving nuclear reimport of proteasomes after mitosis; inside the nucleus AKIRIN2 is itself degraded by proteasomes in a ubiquitin-independent manner, and its loss causes nuclear proteasome depletion with consequent accumulation of substrates such as MYC (PMID:34711951). In a parallel transcriptional role, AKIRIN2 bridges NF-κB/IκB-ζ and other transcription factors to BAF/SWI/SNF chromatin-remodeling complexes via BAF60 subunits, thereby controlling inflammatory gene expression in macrophages, B cell proliferation through Myc and cyclin D2 promoter remodeling, cortical progenitor survival, and myogenic differentiation (PMID:25107474, PMID:26041538, PMID:27871306, PMID:30801883). Loss of AKIRIN2 in postmitotic cortical neurons triggers p53-dependent necroptotic neurodegeneration, as demonstrated by genetic rescue upon Trp53 reduction (PMID:35198879).

Mechanistic history

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

    Identifying AKIRIN2 as a transcriptional repressor established that it could participate directly in promoter-level gene regulation, not solely signal relay, by showing its complex with 14-3-3β represses BCAM transcription.

    Evidence Co-IP of 14-3-3β–AKIRIN2, ChIP at BCAM promoter, luciferase reporter assay in human cells

    PMID:24223164

    Open questions at the time
    • Single target gene (BCAM); genome-wide scope of 14-3-3β–AKIRIN2 repression unknown
    • Structural basis of 14-3-3β–AKIRIN2 interaction not resolved
  2. 2014 High

    Defining the IκB-ζ–AKIRIN2–BAF60 bridge established the first molecular mechanism by which AKIRIN2 couples an NF-κB-family factor to SWI/SNF chromatin remodeling at specific inflammatory gene promoters.

    Evidence Reciprocal Co-IP, ChIP at Il6/Il12b promoters, macrophage-specific knockout, multiple innate immune stimuli

    PMID:25107474

    Open questions at the time
    • Which BAF60 paralog is preferred in vivo not fully resolved
    • Whether AKIRIN2 contacts SWI/SNF subunits beyond BAF60 unknown
  3. 2015 High

    Showing that AKIRIN2 recruits BRG1/SWI/SNF to Myc and Ccnd2 promoters in B cells extended the bridging mechanism beyond innate immunity to adaptive immunity and cell cycle control.

    Evidence B cell-specific conditional knockout, ChIP for BRG1, cell cycle and immunization assays

    PMID:26041538

    Open questions at the time
    • Whether AKIRIN2 also acts through BAF60 in B cells not directly tested
    • Transcription factors upstream of AKIRIN2 at Myc/Ccnd2 in B cells not identified
  4. 2016 High

    Demonstrating that cortex-restricted Akirin2 knockout causes massive progenitor apoptosis and cortical agenesis established AKIRIN2 as essential for cerebral cortex formation and linked it to Wnt3a signaling disruption.

    Evidence Emx1-Cre conditional knockout, EdU labeling, in situ hybridization for Wnt3a and cortical markers

    PMID:27871306

    Open questions at the time
    • Direct molecular target connecting AKIRIN2 to Wnt3a transcription not identified
    • Whether progenitor apoptosis is proteasome- or transcription-dependent unclear
  5. 2017 Medium

    Epistasis experiments in Xenopus positioned AKIRIN2 as an antagonist of Geminin in neural progenitor maintenance, acting through a BAF53a-containing SWI/SNF complex, reinforcing the SWI/SNF-bridging model in neurogenesis.

    Evidence Morpholino knockdown in Xenopus, Co-IP with BAF53a, epistasis with Geminin/NeuroD/Ngnr1

    PMID:28193841

    Open questions at the time
    • Morpholino-based; not confirmed by genetic knockout in Xenopus
    • Direct physical interaction between AKIRIN2 and Geminin not shown
  6. 2019 High

    Conditional knockout in somitic muscle precursors revealed that AKIRIN2 is indispensable for mammalian skeletal muscle formation by preventing Pax3-positive myoblast apoptosis and enabling myogenin expression, broadening its developmental roles beyond the nervous and immune systems.

    Evidence Sim1-Cre conditional knockout, Western blot for myogenin/MHC, in vitro myoblast differentiation

    PMID:30801883

    Open questions at the time
    • Whether AKIRIN2 acts via SWI/SNF at myogenic promoters not directly tested by ChIP
    • Relationship between proteasome import function and myogenesis not addressed
  7. 2021 High

    A CRISPR screen followed by direct binding and imaging studies revealed a fundamentally new function: AKIRIN2 homodimers bind 20S proteasomes and mediate their nuclear import after mitosis, explaining why AKIRIN2 loss depletes nuclear proteasomes and stabilizes substrates like MYC.

    Evidence CRISPR screen, Co-IP, intracellular immunostaining, FACS, live imaging in human cells

    PMID:34711951

    Open questions at the time
    • Structural basis of proteasome binding not yet resolved at atomic level
    • Relative contribution of proteasome import vs. transcriptional roles to cell viability unknown
  8. 2022 High

    Genetic epistasis showed that neurodegeneration caused by neuronal AKIRIN2 loss proceeds through p53-dependent necroptosis, positioning p53 downstream of AKIRIN2 in postmitotic neuron survival.

    Evidence Neuron-specific conditional knockout, RNA-seq, genetic rescue by Trp53 reduction

    PMID:35198879

    Open questions at the time
    • Whether p53 accumulation is due to impaired proteasomal degradation or transcriptional de-repression not distinguished
    • Whether necroptosis mediators (RIPK1/3, MLKL) are directly regulated by AKIRIN2 unknown
  9. 2024 High

    Cryo-EM and saturation mutagenesis resolved how AKIRIN2 scaffolds proteasome import: a wing-helix motif stabilizes proteasome binding, AKIRIN2 homodimers recruit IPO9, and a second AKIRIN2 dimer amplifies importin recruitment; upon nuclear entry, RanGTP dissociates importins and AKIRIN2 is degraded ubiquitin-independently by the proteasome it delivered.

    Evidence Cryo-EM structure, protein-wide saturation mutagenesis, biochemical reconstitution, FACS-based screens (preprint)

    PMID:bio_10.1101_2024.11.08.622636

    Open questions at the time
    • Preprint; awaits peer review
    • How AKIRIN2 degradation is triggered specifically inside the nucleus not fully elucidated
    • Whether other importins beyond IPO9 participate in the complex in vivo not settled

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how AKIRIN2's two major functions — proteasome nuclear import and SWI/SNF-mediated transcriptional regulation — are coordinated, whether they are deployed in the same or distinct cellular contexts, and which function accounts for the apoptotic and proliferative phenotypes observed across tissues.
  • No study has separated proteasome-import and transcription-bridging functions using separation-of-function mutants
  • No structural data for AKIRIN2–BAF60 or AKIRIN2–IκB-ζ interfaces
  • Relative contribution of each function to disease-relevant phenotypes untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0140110 transcription regulator activity 3 GO:0005198 structural molecule activity 2
Localization
GO:0005634 nucleus 5
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-4839726 Chromatin organization 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-168256 Immune System 2 R-HSA-9609507 Protein localization 2 GO:0005634 nucleus 1
Partners
BAF53ABAF60BRG1IPO9NFKBIZTP53YWHAB
Complex memberships
20S proteasome import complexBAF/SWI/SNF chromatin remodeling complex

Evidence

Reading pass · 12 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 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 imaging, loss-of-function experiments with defined molecular phenotype Nature High 34711951
2024 AKIRIN2 acts as a multivalent scaffold protein for proteasome nuclear import: a wing helix in its disordered region stabilizes proteasome interactions; AKIRIN2 homodimers recruit importin IPO9, which facilitates binding of a second AKIRIN2 homodimer that recruits additional importins, amplifying nuclear localization signals for proteasome translocation. Inside the nucleus, RanGTP dissociates importins and AKIRIN2 is degraded by the proteasome in a ubiquitin-independent manner. Protein-wide saturation mutagenesis screens, cryo-EM, biochemical reconstitution, FACS- and microscopy-based genetic screens bioRxivpreprint High bio_10.1101_2024.11.08.622636
2014 AKIRIN2 bridges NF-κB and the SWI/SNF chromatin remodeling complex by interacting with BAF60 proteins and IκB-ζ (which forms a complex with NF-κB p50). This IκB-ζ–AKIRIN2–BAF60 complex is essential for TLR-, RIG-I-, and Listeria-mediated expression of proinflammatory genes (Il6, Il12b) in macrophages. Recruitment of AKIRIN2 and IκB-ζ to the Il6 promoter is mutually dependent. Co-immunoprecipitation, chromatin immunoprecipitation, macrophage-specific knockout, gene expression analysis, infection model The EMBO journal High 25107474
2015 AKIRIN2 is required for B cell cycle progression and humoral immune responses by controlling SWI/SNF complex recruitment (BRG1/Brg1) to the Myc and Ccnd2 promoters; B cell-specific Akirin2 knockout impairs cyclin D and c-Myc expression and causes proliferation defects and increased apoptosis. B cell-specific conditional knockout (Cd19-Cre), chromatin immunoprecipitation at Myc and Ccnd2 promoters, cell cycle analysis, in vivo immunization assays Journal of immunology High 26041538
2016 AKIRIN2 is required for embryonic formation of the cerebral cortex; cortex-restricted Akirin2 knockout causes massive apoptosis of early cortical progenitors, failed proliferation, reduced neuron production, and disrupted Wnt3a/cortical hem signaling. Sox2-positive progenitors spill into the lateral ventricle, indicating disrupted apical ventricular surface integrity. Emx1-Cre conditional knockout, immunohistochemistry, EdU labeling, in situ hybridization, cell cycle analysis Neural development High 27871306
2017 AKIRIN2 is required for neural development in Xenopus: knockdown expands Sox2 (neural progenitor) expression and inhibits N-tubulin (differentiated neuron) expression. AKIRIN2 acts antagonistically to Geminin to regulate Sox2 expression, maintains neural precursor state via BAF53a-containing BAF/SWI/SNF complex, and modulates N-tubulin expression upstream of NeuroD and in parallel with Ngnr1. Morpholino knockdown in Xenopus, in situ hybridization, co-immunoprecipitation with BAF53a, epistasis experiments with Geminin/NeuroD/Ngnr1 The Journal of biological chemistry Medium 28193841
2019 AKIRIN2 is required in vivo for mammalian muscle formation: loss of Akirin2 in somitic muscle precursors causes complete absence of forelimb, intercostal, and diaphragm muscles due to apoptosis of Pax3-positive myoblasts, and impairs expression of myogenin and myosin heavy chain differentiation factors. Sim1-Cre conditional knockout, immunohistochemistry, Western blot for differentiation markers, in vitro myoblast differentiation assay Genesis High 30801883
2022 AKIRIN2 loss in excitatory cortical neurons causes progressive neurodegeneration via necroptosis and upregulation of p53 (Trp53) target genes. Genetic reduction of Trp53 rescues neurodegeneration in Akirin2-null neurons, placing p53 pathways downstream of AKIRIN2 in neuronal maintenance. Neuron-specific conditional knockout, transcriptome comparison (RNA-seq), genetic epistasis (Trp53 reduction rescue), histological analysis iScience High 35198879
2013 The 14-3-3β–FBI1/AKIRIN2 complex acts as a transcriptional repressor by binding to the BCAM promoter and repressing its transcription, as shown by luciferase reporter assay and chromatin immunoprecipitation. AKIRIN2 (FBI1) was identified as a direct binding partner of 14-3-3β. Co-immunoprecipitation (14-3-3β pulldown of FBI1/AKIRIN2), luciferase reporter assay, chromatin immunoprecipitation at BCAM promoter, antisense knockdown PloS one Medium 24223164
2018 AKIRIN2 is required for interdigital tissue regression in the mouse limb; knockout in limb epithelium prevents interdigital cell death, increases cell proliferation, and causes soft-tissue syndactyly associated with perdurance of Fgf8 expression in the interdigital ectoderm, indicating AKIRIN2 is required for downregulation of Fgf8 from the apical ectodermal ridge. Epithelium-specific conditional knockout, immunohistochemistry, in situ hybridization for Fgf8, cell death/proliferation assays Scientific reports Medium 30116001
2019 AKIRIN2 induces angiogenesis in cholangiocarcinoma by increasing VEGFA expression through activation of the IL-6/STAT3 signaling pathway, and promotes epithelial-mesenchymal transition; miR-490-3p negatively regulates AKIRIN2 expression at the posttranscriptional level by binding to the 3'-UTR of AKIRIN2 mRNA. Lentiviral overexpression/knockdown, luciferase reporter assay (miR-490-3p binding to AKIRIN2 3'-UTR), in vivo tumor model, western blot for STAT3/VEGFA pathway Cell death & disease Medium 30886152
2024 In sea cucumber (Apostichopus japonicus), AjAkirin2 directly interacts with Aj14-3-3ζ protein (confirmed by GST pull-down and co-IP), positively regulates Aj14-3-3ζ expression, and promotes NF-κB signaling (p65, p105) and inflammatory cytokine expression for antibacterial defense. GST pull-down, co-immunoprecipitation, RNAi knockdown, bacterial challenge survival assay, qPCR Fish & shellfish immunology Low 38685443

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 89 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 37 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 21 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 9 33259930
2015 Effect of porcine Akirin2 on skeletal myosin heavy chain isoform expression. International journal of molecular sciences 9 25686036
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
2014 Molecular cloning, sequence analysis and tissue-specific expression of Akirin2 gene in Tianfu goat. Gene 8 25239665
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
2017 Akirin2 promotes slow myosin heavy chain expression by CaN/NFATc1 signaling in porcine skeletal muscle satellite cells. Oncotarget 5 28223540
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 4 39267282
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