Interleukin-1 receptor-associated kinase 4

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 to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. 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 NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections.

Classification

Family (Pfam)

PF07714 PK_Tyr_Ser-Thr

InterPro

DEATH-like_dom_sf, IRAK4, IRAK4_Death, Kinase-like_dom_sf, LRR_Rcpt-Like_S/T_Kinase, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom

Functional cluster

Serine/Threonine Protein Kinases

Experimental structures · PDB · 93

• 2NRU X-ray 2.00A
• 2NRY X-ray 2.15A
• 2O8Y X-ray 2.40A
• 2OIB X-ray 2.00A
• 2OIC X-ray 2.40A
• 2OID X-ray 2.30A
• 3MOP X-ray 3.40A
• 4RMZ X-ray 2.20A
• 4U97 X-ray 2.65A
• 4U9A X-ray 2.80A
• 4XS2 X-ray 2.73A
• 4Y73 X-ray 2.14A
• … and 81 more

A predicted model is available from AlphaFold.

Gene Ontology · 34

• GO:0009986 cell surface
• GO:0005737 cytoplasm
• GO:0005829 cytosol
• GO:0010008 endosome membrane
• GO:0005615 extracellular space
• GO:0019897 extrinsic component of plasma membrane
• GO:0005634 nucleus
• GO:0005886 plasma membrane
• GO:0005524 ATP binding
• GO:0005149 interleukin-1 receptor binding
• GO:0016301 kinase activity
• GO:0000287 magnesium ion binding
• 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:0019221 cytokine-mediated signaling pathway
• 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:0002446 neutrophil mediated immunity
• GO:1990266 neutrophil migration
• GO:0044546 NLRP3 inflammasome complex assembly
• GO:0043123 positive regulation of canonical NF-kappaB signal transduction
• GO:0048661 positive regulation of smooth muscle cell proliferation
• GO:0043405 regulation of MAP kinase activity
• GO:0008063 Toll 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

Disease associations

• immunodeficiency 67 MONDO:0011888

Drugs targeting this protein · 1

• ZIMLOVISERTIB inhibitor

Related proteins · sequence + function similarity

• Interleukin-1 receptor-associated kinase 4 0.98
• Interleukin-1 receptor-associated kinase 4 0.97
• Pelle-like serine/threonine-protein kinase pik-1 0.85
• Serine/threonine-protein kinase pelle 0.85
• Dual specificity protein kinase shkC 0.74
• Probable serine/threonine-protein kinase PBL26 0.72
• Probable serine/threonine-protein kinase PBL23 0.71
• Tyrosine-protein kinase CSK 0.70
• Tyrosine-protein kinase SPK-1 0.70
• Dual specificity protein kinase shkA 0.70
• Probable serine/threonine-protein kinase PBL7 0.70
• Stress-activated protein kinase alpha 0.70

Co-cited proteins · studied together in the literature

• Interleukin-1 receptor-associated kinase 1 8 shared papers
• Interleukin-1 receptor-associated kinase 3 1 shared papers
• Interleukin-1 receptor-associated kinase-like 2 1 shared papers
• Myeloid differentiation primary response protein MyD88 4 shared papers
• Interleukin-1 receptor-associated kinase 4 2 shared papers
• E3 ubiquitin-protein ligase pellino homolog 1 3 shared papers
• NF-kappa-B essential modulator 1 shared papers
• E3 ubiquitin-protein ligase pellino homolog 3 1 shared papers
• Toll/interleukin-1 receptor domain-containing adapter protein 1 shared papers
• TNF receptor-associated factor 6 4 shared papers
• E3 ubiquitin-protein ligase pellino homolog 2 1 shared papers
• Interleukin-1 receptor-like 1 1 shared papers

Literature · 36 cited papers

• Dimeric Structure of the Pseudokinase IRAK3 Suggests an Allosteric Mechanism for Negative Regulation. Structure · 2021
• Functional assessment of the mutational effects of human IRAK4 and MyD88 genes. Mol. Immunol. · 2014
• Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
• N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB. Proc. Natl. Acad. Sci. U.S.A. · 2012
• Natural loss-of-function mutation of myeloid differentiation protein 88 disrupts its ability to form Myddosomes. J. Biol. Chem. · 2011
• What the Myddosome structure tells us about the initiation of innate immunity. Trends Immunol. · 2011
• Initial characterization of the human central proteome. BMC Syst. Biol. · 2011
• Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine (Baltimore) · 2010
• Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature · 2010
• IRAK1 and IRAK4 promote phosphorylation, ubiquitination, and degradation of MyD88 adaptor-like (Mal). J. Biol. Chem. · 2010
• Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci. Signal. · 2010
• Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions. Sci. Signal. · 2009
• … and 24 more in the literature graph