IRAK1

Interleukin-1 receptor-associated kinase 1 (IRAK-1) is an enzyme in humans encoded by the IRAK1 gene. IRAK-1 plays an important role in the regulation of the expression of inflammatory genes by immune cells, such as monocytes and macrophages, which in turn help the immune system in eliminating bacteria, viruses, and other pathogens. IRAK-1 is part of the IRAK family consisting of IRAK-1, IRAK-2, IRAK-3, and IRAK-4, and is activated by inflammatory molecules released by signaling pathways during pathogenic attack. IRAK-1 is classified as a kinase enzyme, which regulates pathways in both innate and adaptive immune systems.

IRAK1
Identifiers
Aliases	IRAK1, IRAK, pelle, interleukin 1 receptor associated kinase 1
External IDs	OMIM: 300283; MGI: 107420; HomoloGene: 37496; GeneCards: IRAK1; OMA:IRAK1 - orthologs
Gene location (Human) Chr. X chromosome (human) Band Xq28 Start 154,010,506 bp End 154,019,902 bp
Gene location (Mouse) Chr. X chromosome (mouse) Band X A7.3|X 37.61 cM Start 73,057,520 bp End 73,067,524 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in parotid gland pancreatic ductal cell endothelial cell gingival epithelium periodontal fiber duodenum epithelium of esophagus mucosa of ileum stromal cell of endometrium granulocyte Top expressed in lacrimal gland parotid gland submandibular gland lobe of prostate Paneth cell islet of Langerhans seminal vesicula tunica media of zone of aorta tunica adventitia of aorta body of femur More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity protein kinase activity nucleotide binding heat shock protein binding protein homodimerization activity kinase activity NF-kappaB-inducing kinase activity protein binding protein heterodimerization activity ATP binding protein serine/threonine kinase activity Cellular component membrane lipid droplet plasma membrane endosome membrane interleukin-1 receptor complex nucleus cytoplasm cytosol Biological process cellular response to heat response to interleukin-1 positive regulation of MAP kinase activity regulation of cytokine-mediated signaling pathway phosphorylation cytokine-mediated signaling pathway immune system process ageing negative regulation of apoptotic process activation of NF-kappaB-inducing kinase activity MyD88-dependent toll-like receptor signaling pathway toll-like receptor signaling pathway positive regulation of transcription, DNA-templated protein phosphorylation JNK cascade response to lipopolysaccharide transmembrane receptor protein serine/threonine kinase signaling pathway positive regulation of NF-kappaB transcription factor activity protein complex oligomerization positive regulation of I-kappaB kinase/NF-kappaB signaling protein autophosphorylation toll-like receptor 9 signaling pathway cellular response to lipopolysaccharide negative regulation of NF-kappaB transcription factor activity nucleotide-binding oligomerization domain containing signaling pathway positive regulation of type I interferon production cellular response to hypoxia lipopolysaccharide-mediated signaling pathway signal transduction positive regulation of smooth muscle cell proliferation toll-like receptor 4 signaling pathway toll-like receptor 2 signaling pathway innate immune response type I interferon signaling pathway viral process interleukin-1-mediated signaling pathway intracellular signal transduction positive regulation of NIK/NF-kappaB signaling positive regulation of leukocyte adhesion to vascular endothelial cell Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3654 16179 Ensembl ENSG00000184216 ENSMUSG00000031392 UniProt P51617 Q62406 RefSeq (mRNA) NM_001025242 NM_001025243 NM_001569 NM_001177973 NM_001177974 NM_001177975 NM_001177976 NM_008363 RefSeq (protein) NP_001020413 NP_001020414 NP_001560 NP_001171444 NP_001171445 NP_001171446 NP_001171447 NP_032389 Location (UCSC) Chr X: 154.01 – 154.02 Mb Chr X: 73.06 – 73.07 Mb PubMed search
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Structure

IRAK-1 contains an N-terminal death domain (DD), a ProST domain, a centrally located kinase domain, and a C-terminal domain. The DD on IRAK-1 acts as an interaction platform for other DD-containing protein, most notably the adaptor protein myeloid differentiation factor 88, MyD88.

The proST domain contains serine, proline, and threonine amino acid residues and is used to facilitate IRAK-1 interaction with other IRAK family members or proteins. For example, auto-phosphorylation may occur multiple times in the ProST domain, which allows IRAK-1 to dissociate from the MyD88 bound to the DD while maintaining interactions with downstream proteins such as TNF receptor-associated factor 6 (TRAF-6) to initiate further pathway signaling.

Moreover, IRAK-1 contains an invariant lysine within the centrally located kinase domain. The invariant lysine acts as a binding site for ATP and a mediator for catalytic function and kinase activity.

IRAK-1 also contains a tyrosine residue (Tyr²⁶²) that conformationally changes the active site of the IRAK-1 by inhibiting the hydrophilic pocket behind the binding site and thereby allows the IRAK-1 to remain in an active state. For example, ATP binding to the IRAK-1 binding site can readily occur in the presence of Tyr²⁶⁶, because Tyr²⁶⁶ will occupy the hydrophilic pocket where ATP competitive inhibitors may bind and disrupt catalytic function.

Activation

In the presence of foreign pathogens, IRAK-1 induced signaling pathways can be activated by Toll-like receptors (TLRs) or by interleukin-1 family receptors (IL-1R) in response. TLRs recognize pathogen-associated molecular patterns (PAMPs) expressed on bacteria and IL-1Rs recognize and bind pro-inflammatory cytokines of the IL-1 family. Both the TLR and IL-1R mediate a signaling cascade that involves MyD88 binding to the receptor, oligomerization of the MyD88, recruitment of IRAK-1 via the DD, multimerization of IRAK-1, and ultimately kinase activation and further downstream signaling.

IRAK-1 can also be activated upon interaction with other IRAK family members. IRAK-1 and IRAK-4 can activate each other by using the DD as a platform for MyD88. IRAK-4 first phosphorylates IRAK-1 which catalyzes an IRAK-1 auto-phosphorylation cascade, occurring in three steps. IRAK-1 is first phosphorylated at Thr209, causing a conformational change. Then, IRAK-1 is phosphorylated at Thr387 rendering IRAK-1 fully active. Finally, auto-phosphorylation at several residues in the proST region stimulates IRAK-1 release from the receptor complex.

Function

The IRAK-1 encodes the interleukin-1 receptor-associated kinase 1, which is a serine-threonine protein kinase that is associated with the interleukin-1 receptor (IL1R) upon stimulation. IRAK-1 is required for pro-inflammatory cytokine production downstream of TLR and IL-1R signaling pathways. Moreover, IRAK-1 is responsible for IL1-induced up-regulation of the transcriptional factor NF-kappa B. Upon binding with its receptor, IRAK-1 becomes activated, as described in Activation, and then dissociates from its receptor complex. IRAK-1 dissociates from the receptor alongside of TRAF6 - a ubiquitin E3 ligase that intermediates between various types of receptors for exogenous or endogenous mediators and activation of transcriptional responses via NF-kappa B and MAPK pathways. IRAK-1 and TRAF-6 then bind to TAK-1 binding protein-1 (TAB-1), followed by binding to transforming growth factor-β-activated kinase (TAK-1) and TAB-2, forming a new complex. This complex then translocates into the cytoplasm wherein it associates with ubiquitin ligases such as ubiquitin conjugating enzyme-13 UBC-13 and ubiquitin conjugating enzyme E2 variant-1(UEV-1a), leading to the ubiquitination and degradation of TRAF-6. TAK-1 is then activated and phosphorylation of the inhibitor of κB kinase (IKK) complex, consisting of IKKα, IKKβ, and IKKγ, occurs. MAPKs are also activated in the process. Finally, NF-κB is activated to regulate the transcription of pro-inflammatory genes. Alternatively, IRAK-1 activation of the NF-κB pathway can be regulated by the ubiquitination of Lys¹³⁴ and Lys¹⁸⁰.

Alternatively spliced transcript variants encoding different isoforms have been found for the IRAK1 gene. Currently, there are three differentially spliced variants of IRAK1 - IRAK1, IRAK1b, and IRAK1c. IRAK1 was observed to undergo sumoylation, promoting its translocation to the nucleus instead of the cytoplasm upon pathogenic attack. IRAK1c, notably, remains stable upon sumoylation, does not undergo modification under the same circumstances and localizes only to the cytoplasm.

IRAK-1 kinase activity is not the sole protein involved in pro-inflammatory immune responses, however, it serves as an adaptor protein that effectively binds MyD88, IRAK-4, the toll-interacting proteins (TOLLIP) together to form a complex that induces IL-1R-mediated NF-κB activation.

Signaling pathway of toll-like receptors. Dashed grey lines represent unknown associations

Regulation

IRAK-1 activity is regulated during its activation and function. Auto-phosphorylation plays a role in IRAK-1 activation (see Activation), and also mediates proteasome-mediated degradation which results in the loss of the IRAK1 protein. Alternatively, IRAK-1 may be regulated on the transcriptional level. The IRAK-1b splice variant lacks kinase activity and is resistant to proteasome-mediated degradation. Moreover, IRAK-1c splice variant has a truncated and thus mutated sequence at the C-terminus of its kinase domain and acts a negative regulator of the TLR and IL-1R signaling pathways.

Interactions

IRAK1 has been shown to interact with the following proteins:

• CHUK
• IKBKG
• IKK2,
• Myd88
• NEMO
• SOCS1
• STAT3
• TRAF6
• UBC,
• TOLLIP
• TLR4

Clinical significance

IRAK-1 signaling is involved in rheumatoid arthritis. Moreover, IRAK-1 plays a significant role in cancer.

Further reading

• Auron PE (1999). "The interleukin 1 receptor: ligand interactions and signal transduction". Cytokine & Growth Factor Reviews. 9 (3–4): 221–237. doi:10.1016/S1359-6101(98)00018-5. PMID 9918122.
• Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV (October 1996). "TRAF6 is a signal transducer for interleukin-1". Nature. 383 (6599): 443–446. Bibcode:1996Natur.383..443C. doi:10.1038/383443a0. PMID 8837778. S2CID 4269027.
• Brenner V, Nyakatura G, Rosenthal A, Platzer M (August 1997). "Genomic organization of two novel genes on human Xq28: compact head to head arrangement of IDH gamma and TRAP delta is conserved in rat and mouse". Genomics. 44 (1): 8–14. doi:10.1006/geno.1997.4822. PMID 9286695.
• Huang J, Gao X, Li S, Cao Z (November 1997). "Recruitment of IRAK to the interleukin 1 receptor complex requires interleukin 1 receptor accessory protein". Proceedings of the National Academy of Sciences of the United States of America. 94 (24): 12829–12832. Bibcode:1997PNAS...9412829H. doi:10.1073/pnas.94.24.12829. PMC 24223. PMID 9371760.
• Muzio M, Natoli G, Saccani S, Levrero M, Mantovani A (June 1998). "The human toll signaling pathway: divergence of nuclear factor kappaB and JNK/SAPK activation upstream of tumor necrosis factor receptor-associated factor 6 (TRAF6)". The Journal of Experimental Medicine. 187 (12): 2097–2101. doi:10.1084/jem.187.12.2097. PMC 2212359. PMID 9625770.
• Maschera B, Ray K, Burns K, Volpe F (April 1999). "Overexpression of an enzymically inactive interleukin-1-receptor-associated kinase activates nuclear factor-kappaB". The Biochemical Journal. 339 (2): 227–231. doi:10.1042/0264-6021:3390227. PMC 1220149. PMID 10191251.
• Wesche H, Gao X, Li X, Kirschning CJ, Stark GR, Cao Z (July 1999). "IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family". The Journal of Biological Chemistry. 274 (27): 19403–19410. doi:10.1074/jbc.274.27.19403. PMID 10383454.
• Yang RB, Mark MR, Gurney AL, Godowski PJ (July 1999). "Signaling events induced by lipopolysaccharide-activated toll-like receptor 2". Journal of Immunology. 163 (2): 639–643. doi:10.4049/jimmunol.163.2.639. PMID 10395652.
• Thomas JA, Allen JL, Tsen M, Dubnicoff T, Danao J, Liao XC, et al. (July 1999). "Impaired cytokine signaling in mice lacking the IL-1 receptor-associated kinase". Journal of Immunology. 163 (2): 978–984. doi:10.4049/jimmunol.163.2.978. PMID 10395695.
• Reichwald K, Thiesen J, Wiehe T, Weitzel J, Poustka WA, Rosenthal A, et al. (March 2000). "Comparative sequence analysis of the MECP2-locus in human and mouse reveals new transcribed regions". Mammalian Genome. 11 (3): 182–190. doi:10.1007/s003350010035. PMID 10723722. S2CID 15901911.
• Burns K, Clatworthy J, Martin L, Martinon F, Plumpton C, Maschera B, et al. (June 2000). "Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor". Nature Cell Biology. 2 (6): 346–351. doi:10.1038/35014038. PMID 10854325. S2CID 32036101.
• Böl G, Kreuzer OJ, Brigelius-Flohé R (July 2000). "Translocation of the interleukin-1 receptor-associated kinase-1 (IRAK-1) into the nucleus". FEBS Letters. 477 (1–2): 73–78. doi:10.1016/S0014-5793(00)01759-2. PMID 10899313.
• Hartley JL, Temple GF, Brasch MA (November 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–1795. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
• Vig E, Green M, Liu Y, Yu KY, Kwon HJ, Tian J, et al. (March 2001). "SIMPL is a tumor necrosis factor-specific regulator of nuclear factor-kappaB activity". The Journal of Biological Chemistry. 276 (11): 7859–7866. doi:10.1074/jbc.M010399200. PMID 11096118.
• Li X, Commane M, Jiang Z, Stark GR (April 2001). "IL-1-induced NFkappa B and c-Jun N-terminal kinase (JNK) activation diverge at IL-1 receptor-associated kinase (IRAK)". Proceedings of the National Academy of Sciences of the United States of America. 98 (8): 4461–4465. Bibcode:2001PNAS...98.4461L. doi:10.1073/pnas.071054198. PMC 31857. PMID 11287640.
• Jensen LE, Whitehead AS (August 2001). "IRAK1b, a novel alternative splice variant of interleukin-1 receptor-associated kinase (IRAK), mediates interleukin-1 signaling and has prolonged stability". The Journal of Biological Chemistry. 276 (31): 29037–29044. doi:10.1074/jbc.M103815200. PMID 11397809.
• Qian Y, Commane M, Ninomiya-Tsuji J, Matsumoto K, Li X (November 2001). "IRAK-mediated translocation of TRAF6 and TAB2 in the interleukin-1-induced activation of NFkappa B". The Journal of Biological Chemistry. 276 (45): 41661–41667. doi:10.1074/jbc.M102262200. PMID 11518704.