Interleukin-1 receptor-associated kinase 1

Function

Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3.

Classification

Family (Pfam)

PF00531 Death, PF00069 Pkinase

InterPro

DEATH-like_dom_sf, Death_dom, Death_IRAK1, Kinase-like_dom_sf, Prot_kinase_dom, Protein_kinase_ATP_BS, Ser/Thr_kinase_AS

Functional cluster

Eukaryotic Transcription Factors & related

Experimental structures · PDB · 1

• 6BFN X-ray 2.26A

A predicted model is available from AlphaFold.

Gene Ontology · 47

• GO:0009986 cell surface
• GO:0005737 cytoplasm
• GO:0005829 cytosol
• GO:0010008 endosome membrane
• GO:0005811 lipid droplet
• GO:0005654 nucleoplasm
• GO:0005634 nucleus
• GO:0005886 plasma membrane
• GO:0032991 protein-containing complex
• GO:0005524 ATP binding
• GO:0031072 heat shock protein binding
• GO:0042802 identical protein binding
• GO:0016301 kinase activity
• GO:0046982 protein heterodimerization activity
• GO:0042803 protein homodimerization activity
• GO:0004672 protein kinase activity
• GO:0019901 protein kinase binding
• GO:0106310 protein serine kinase activity
• GO:0004674 protein serine/threonine kinase activity
• GO:0007249 canonical NF-kappaB signal transduction
• GO:0034605 cellular response to heat
• GO:0071456 cellular response to hypoxia
• GO:0045087 innate immune response
• GO:0070498 interleukin-1-mediated signaling pathway
• GO:0038172 interleukin-33-mediated signaling pathway
• GO:0035556 intracellular signal transduction
• GO:0007254 JNK cascade
• GO:0031663 lipopolysaccharide-mediated signaling pathway
• GO:0002755 MyD88-dependent toll-like receptor signaling pathway
• GO:0043124 negative regulation of canonical NF-kappaB signal transduction
• GO:0044546 NLRP3 inflammasome complex assembly
• GO:0043123 positive regulation of canonical NF-kappaB signal transduction
• GO:1904996 positive regulation of leukocyte adhesion to vascular endothelial cell
• GO:0048661 positive regulation of smooth muscle cell proliferation
• GO:0032481 positive regulation of type I interferon production
• GO:0046777 protein autophosphorylation
• GO:0001959 regulation of cytokine-mediated signaling pathway
• GO:0006355 regulation of DNA-templated transcription
• GO:0043405 regulation of MAP kinase activity
• GO:0070555 response to interleukin-1
• GO:0032496 response to lipopolysaccharide
• GO:0008063 Toll signaling pathway
• GO:0034134 toll-like receptor 2 signaling pathway
• GO:0034142 toll-like receptor 4 signaling pathway
• GO:0034162 toll-like receptor 9 signaling pathway
• GO:0002224 toll-like receptor signaling pathway
• GO:0060337 type I interferon-mediated signaling pathway

Drugs targeting this protein · 1

• PACRITINIB CITRATE inhibitor

Related proteins · sequence + function similarity

• Interleukin-1 receptor-associated kinase 1 0.99
• Interleukin-1 receptor-associated kinase 1 0.95
• Dual specificity testis-specific protein kinase 1 0.88
• Dual specificity testis-specific protein kinase 1 0.87
• Dual specificity testis-specific protein kinase 1 0.87
• Interleukin-1 receptor-associated kinase-like 2 0.85
• Interleukin-1 receptor-associated kinase-like 2 0.84
• Anti-Muellerian hormone type-2 receptor 0.83
• Anti-Muellerian hormone type-2 receptor 0.83
• Anti-Muellerian hormone type-2 receptor 0.83
• Interleukin-1 receptor-associated kinase-like 2 0.82
• Anti-Muellerian hormone type-2 receptor 0.82

Co-cited proteins · studied together in the literature

• Interleukin-1 receptor-associated kinase 4 8 shared papers
• E3 ubiquitin-protein ligase pellino homolog 2 2 shared papers
• Interleukin-1 receptor-associated kinase 1 3 shared papers
• TNF receptor-associated factor 6 7 shared papers
• Interleukin-1 receptor-associated kinase 4 2 shared papers
• E3 ubiquitin-protein ligase pellino homolog 3 2 shared papers
• Toll-interacting protein 1 shared papers
• E3 ubiquitin-protein ligase pellino homolog 1 4 shared papers
• Small hydrophobic protein 1 shared papers
• Protein kinase C iota type 1 shared papers
• Structural polyprotein 1 shared papers
• Innate immunity activator protein 1 shared papers

Literature · 37 cited papers

• The Alphaviral Capsid Protein Inhibits IRAK1-Dependent TLR Signaling. Viruses · 2021
• PELI1 selectively targets kinase-active RIP3 for ubiquitylation-dependent proteasomal degradation. Mol. Cell · 2018
• Mumps virus SH protein inhibits NF-kappaB activation by interacting with tumor necrosis factor receptor 1, interleukin-1 receptor 1, and Toll-like receptor 3 complexes. J. Virol. · 2017
• An inflammatory bowel disease-risk variant in INAVA decreases pattern recognition receptor-induced outcomes. J. Clin. Invest. · 2017
• Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
• Initial characterization of the human central proteome. BMC Syst. Biol. · 2011
• IRAK1 and IRAK4 promote phosphorylation, ubiquitination, and degradation of MyD88 adaptor-like (Mal). J. Biol. Chem. · 2010
• Direct activation of protein kinases by unanchored polyubiquitin chains. Nature · 2009
• The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling. Trends Immunol. · 2009
• Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol. Cell · 2008
• The interleukin-1 receptor associated kinase 1 contributes to the regulation of NFAT. Mol. Immunol. · 2008
• A quantitative atlas of mitotic phosphorylation. Proc. Natl. Acad. Sci. U.S.A. · 2008
• … and 25 more in the literature graph