NF-kappa-B inhibitor alpha

Function

Inhibits the activity of dimeric NF-kappa-B/REL complexes by trapping REL (RELA/p65 and NFKB1/p50) dimers in the cytoplasm by masking their nuclear localization signals. On cellular stimulation by immune and pro-inflammatory responses, becomes phosphorylated promoting ubiquitination and degradation, enabling the dimeric RELA to translocate to the nucleus and activate transcription.

Classification

Family (Pfam)

PF12796 Ank_2

InterPro

Ankyrin_rpt, Ankyrin_rpt-contain_sf, NF-kappa-B_inhibitor

Functional cluster

Eukaryotic Transcription Factors & related

Experimental structures · PDB · 4

• 1IKN X-ray 2.30A
• 1NFI X-ray 2.70A
• 6TTU EM 3.70A
• 6Y1J X-ray 1.13A

A predicted model is available from AlphaFold.

Gene Ontology · 30

• GO:0005737 cytoplasm
• GO:0005829 cytosol
• GO:0033256 I-kappaB/NF-kappaB complex
• GO:0005654 nucleoplasm
• GO:0005634 nucleus
• GO:0019899 enzyme binding
• GO:0042802 identical protein binding
• GO:0140313 molecular sequestering activity
• GO:0051059 NF-kappaB binding
• GO:0008139 nuclear localization sequence binding
• GO:0140311 protein sequestering activity
• GO:0140416 transcription regulator inhibitor activity
• GO:0031625 ubiquitin protein ligase binding
• GO:0050853 B cell receptor signaling pathway
• GO:0007249 canonical NF-kappaB signal transduction
• GO:0070417 cellular response to cold
• GO:0070498 interleukin-1-mediated signaling pathway
• GO:0043124 negative regulation of canonical NF-kappaB signal transduction
• GO:0032375 negative regulation of cholesterol transport
• GO:1900016 negative regulation of cytokine production involved in inflammatory response
• GO:0010888 negative regulation of lipid storage
• GO:0010745 negative regulation of macrophage derived foam cell differentiation
• GO:0042308 negative regulation of protein import into nucleus
• GO:0000122 negative regulation of transcription by RNA polymerase II
• GO:0038061 non-canonical NF-kappaB signal transduction
• GO:0050729 positive regulation of inflammatory response
• GO:0045944 positive regulation of transcription by RNA polymerase II
• GO:0060261 positive regulation of transcription initiation by RNA polymerase II
• GO:0034142 toll-like receptor 4 signaling pathway
• GO:0033209 tumor necrosis factor-mediated signaling pathway

Disease associations

• ectodermal dysplasia and immunodeficiency 2 MONDO:0012806

Neighborhood · nearest proteins

Related proteins · sequence + function similarity

• NF-kappa-B inhibitor alpha 0.99
• NF-kappa-B inhibitor alpha 0.99
• NF-kappa-B inhibitor alpha 0.99
• NF-kappa-B inhibitor alpha 0.95
• NF-kappa-B inhibitor epsilon 0.86
• NF-kappa-B inhibitor delta 0.78
• NF-kappa-B inhibitor beta 0.77
• NF-kappa-B inhibitor beta 0.76
• NF-kappa-B inhibitor delta 0.75
• Receptor-interacting serine/threonine-protein kinase 4 0.74
• Receptor-interacting serine/threonine-protein kinase 4 0.74
• NF-kappa-B inhibitor beta 0.73

Co-cited proteins · studied together in the literature

• Ubiquitin carboxyl-terminal hydrolase 39 1 shared papers
• NF-kappa-B inhibitor alpha 1 shared papers
• Replicase polyprotein 1ab 1 shared papers
• NF-kappa-B inhibitor beta 2 shared papers
• F-box/WD repeat-containing protein 11 3 shared papers
• Transcription factor p65 4 shared papers
• Protein arginine N-methyltransferase 2 1 shared papers
• Ubiquitin carboxyl-terminal hydrolase 39 1 shared papers
• Protein FAM76B 1 shared papers
• DDRGK domain-containing protein 1 1 shared papers
• RWD domain-containing protein 3 2 shared papers
• cAMP-dependent protein kinase catalytic subunit alpha 1 shared papers

Literature · 44 cited papers

• FAM76B regulates NF-kappaB-mediated inflammatory pathway by influencing the translocation of hnRNPA2B1. Elife · 2023
• USP39 Regulates NF-kappaB-Mediated Inflammatory Responses through Deubiquitinating K48-Linked IkappaBalpha. J. Immunol. · 2023
• DDRGK1 regulates NF-kappaB activity by modulating IkappaBalpha stability. PLoS ONE · 2013
• In silico structural and functional characterization of the RSUME splice variants. PLoS ONE · 2013
• The cysteine protease domain of porcine reproductive and respiratory syndrome virus nonstructural protein 2 possesses deubiquitinating and interferon antagonism functions. J. Virol. · 2010
• Thrombin and collagen induce a feedback inhibitory signaling pathway in platelets involving dissociation of the catalytic subunit of protein kinase A from an NFkappaB-IkappaB complex. J. Biol. Chem. · 2010
• Priming and extending: a UbcH5/Cdc34 E2 handoff mechanism for polyubiquitination on a SCF substrate. Mol. Cell · 2010
• The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1 and activates NF-kappaB through its N-terminal fragment. Blood · 2008
• A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated with ectodermal dysplasia with immunodeficiency. Hum. Mutat. · 2008
• RSUME, a small RWD-containing protein, enhances SUMO conjugation and stabilizes HIF-1alpha during hypoxia. Cell · 2007
• Posttranslational hydroxylation of ankyrin repeats in IkappaB proteins by the hypoxia-inducible factor (HIF) asparaginyl hydroxylase, factor inhibiting HIF (FIH). Proc. Natl. Acad. Sci. U.S.A. · 2006
• Protein methyltransferase 2 inhibits NF-kappaB function and promotes apoptosis. Mol. Cell. Biol. · 2006
• … and 32 more in the literature graph