IRAK1

Interleukin-1 receptor-associated kinase 1 (IRAK-1) is an enzyme in humans encoded by the IRAK1 gene.{{cite journal | vauthors = Muzio M, Ni J, Feng P, Dixit VM | title = IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling | journal = Science | volume = 278 | issue = 5343 | pages = 1612–1615 | date = November 1997 | pmid = 9374458 | doi = 10.1126/science.278.5343.1612 | bibcode = 1997Sci...278.1612M }}{{cite journal | vauthors = Cao Z, Henzel WJ, Gao X | title = IRAK: a kinase associated with the interleukin-1 receptor | journal = Science | volume = 271 | issue = 5252 | pages = 1128–1131 | date = February 1996 | pmid = 8599092 | doi = 10.1126/science.271.5252.1128 | s2cid = 42977425 | bibcode = 1996Sci...271.1128C }} 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.{{cite journal | vauthors = Jain A, Kaczanowska S, Davila E | title = IL-1 Receptor-Associated Kinase Signaling and Its Role in Inflammation, Cancer Progression, and Therapy Resistance | journal = Frontiers in Immunology | volume = 5 | pages = 553 | date = 2014 | pmid = 25452754 | doi = 10.3389/fimmu.2014.00553 | pmc = 4233944 | doi-access = free }} IRAK-1 is classified as a kinase enzyme, which regulates pathways in both innate and adaptive immune systems.{{cite journal | vauthors = Deng Y, Hahn BH, Tsao BP |title=Systemic Lupus Erythematosus |journal=Emery and Rimoin's Principles and Practice of Medical Genetics |date=2013 |pages=1–22 |doi=10.1016/B978-0-12-383834-6.00081-1 |isbn=9780123838346 }}

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.{{cite journal | vauthors = Wang Z, Wesche H, Stevens T, Walker N, Yeh WC | title = IRAK-4 inhibitors for inflammation | journal = Current Topics in Medicinal Chemistry | volume = 9 | issue = 8 | pages = 724–737 | date = May 2009 | pmid = 19689377 | pmc = 3182414 | doi = 10.2174/156802609789044407 }}

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.{{cite journal | vauthors = Wang L, Qiao Q, Ferrao R, Shen C, Hatcher JM, Buhrlage SJ, Gray NS, Wu H | display-authors = 6 | title = Crystal structure of human IRAK1 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 51 | pages = 13507–13512 | date = December 2017 | pmid = 29208712 | pmc = 5754798 | doi = 10.1073/pnas.1714386114 | bibcode = 2017PNAS..11413507W | doi-access = free }}

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.{{cite journal | vauthors = Dainichi T, Matsumoto R, Mostafa A, Kabashima K | title = Immune Control by TRAF6-Mediated Pathways of Epithelial Cells in the EIME (Epithelial Immune Microenvironment) | journal = Frontiers in Immunology | volume = 10 | pages = 1107 | date = 2019 | pmid = 31156649 | doi = 10.3389/fimmu.2019.01107 | pmc = 6532024 | doi-access = free }} 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.{{cite journal | vauthors = Kong F, Liu Z, Jain VG, Shima K, Suzuki T, Muglia LJ, Starczynowski DT, Pasare C, Bhattacharyya S | display-authors = 6 | title = Inhibition of IRAK1 Ubiquitination Determines Glucocorticoid Sensitivity for TLR9-Induced Inflammation in Macrophages | journal = Journal of Immunology | volume = 199 | issue = 10 | pages = 3654–3667 | date = November 2017 | pmid = 29038250 | doi = 10.4049/jimmunol.1700443 | pmc = 5672817 }}

Alternatively spliced transcript variants encoding different isoforms have been found for the IRAK1 gene.{{cite web | title = Entrez Gene: IRAK1 interleukin-1 receptor-associated kinase 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3654}} 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.{{cite journal | vauthors = Su J, Richter K, Zhang C, Gu Q, Li L | title = Differential regulation of interleukin-1 receptor associated kinase 1 (IRAK1) splice variants | journal = Molecular Immunology | volume = 44 | issue = 5 | pages = 900–905 | date = February 2007 | pmid = 16690127 | doi = 10.1016/j.molimm.2006.03.021 }}

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){{Cite web |title=TOLLIP toll interacting protein [Homo sapiens (human)] - Gene - NCBI |url=https://www.ncbi.nlm.nih.gov/gene/54472 |access-date=2022-03-05 |website=www.ncbi.nlm.nih.gov}} together to form a complex that induces IL-1R-mediated NF-κB activation.

Image:Toll-like receptor pathways revised.jpg

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.{{cite journal | vauthors = Gottipati S, Rao NL, Fung-Leung WP | title = IRAK1: a critical signaling mediator of innate immunity | journal = Cellular Signalling | volume = 20 | issue = 2 | pages = 269–276 | date = February 2008 | pmid = 17890055 | doi = 10.1016/j.cellsig.2007.08.009 }} 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{{cite journal | vauthors = Windheim M, Stafford M, Peggie M, Cohen P | title = Interleukin-1 (IL-1) induces the Lys63-linked polyubiquitination of IL-1 receptor-associated kinase 1 to facilitate NEMO binding and the activation of IkappaBalpha kinase | journal = Molecular and Cellular Biology | volume = 28 | issue = 5 | pages = 1783–1791 | date = March 2008 | pmid = 18180283 | pmc = 2258775 | doi = 10.1128/MCB.02380-06 }}{{cite journal | vauthors = Conze DB, Wu CJ, Thomas JA, Landstrom A, Ashwell JD | title = Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activation | journal = Molecular and Cellular Biology | volume = 28 | issue = 10 | pages = 3538–3547 | date = May 2008 | pmid = 18347055 | pmc = 2423148 | doi = 10.1128/MCB.02098-07 }}
IKK2,{{cite journal | vauthors = Vig E, Green M, Liu Y, Yu KY, Kwon HJ, Tian J, Goebl MG, Harrington MA | display-authors = 6 | title = SIMPL is a tumor necrosis factor-specific regulator of nuclear factor-kappaB activity | journal = The Journal of Biological Chemistry | volume = 276 | issue = 11 | pages = 7859–7866 | date = March 2001 | pmid = 11096118 | doi = 10.1074/jbc.M010399200 | doi-access = free }}
Myd88{{cite journal | vauthors = Chen BC, Wu WT, Ho FM, Lin WW | title = Inhibition of interleukin-1beta -induced NF-kappa B activation by calcium/calmodulin-dependent protein kinase kinase occurs through Akt activation associated with interleukin-1 receptor-associated kinase phosphorylation and uncoupling of MyD88 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 27 | pages = 24169–24179 | date = July 2002 | pmid = 11976320 | doi = 10.1074/jbc.M106014200 | doi-access = free }}{{cite journal | vauthors = Wesche H, Gao X, Li X, Kirschning CJ, Stark GR, Cao Z | title = IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family | journal = The Journal of Biological Chemistry | volume = 274 | issue = 27 | pages = 19403–19410 | date = July 1999 | pmid = 10383454 | doi = 10.1074/jbc.274.27.19403 | doi-access = free }}{{cite journal | vauthors = Li S, Strelow A, Fontana EJ, Wesche H | title = IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 8 | pages = 5567–5572 | date = April 2002 | pmid = 11960013 | pmc = 122810 | doi = 10.1073/pnas.082100399 | doi-access = free | bibcode = 2002PNAS...99.5567L }}{{cite journal | vauthors = Fitzgerald KA, Palsson-McDermott EM, Bowie AG, Jefferies CA, Mansell AS, Brady G, Brint E, Dunne A, Gray P, Harte MT, McMurray D, Smith DE, Sims JE, Bird TA, O'Neill LA | display-authors = 6 | title = Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction | journal = Nature | volume = 413 | issue = 6851 | pages = 78–83 | date = September 2001 | pmid = 11544529 | doi = 10.1038/35092578 | s2cid = 4333764 | bibcode = 2001Natur.413...78F }}
NEMO{{cite web| work = GeneCards Human Gene Database |title=IRAK1 Gene {{!}} IRAK1 Protein {{!}} IRAK1 Antibody|url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=IRAK1 }}
SOCS1
STAT3
TRAF6{{cite journal | vauthors = Qian Y, Commane M, Ninomiya-Tsuji J, Matsumoto K, Li X | title = IRAK-mediated translocation of TRAF6 and TAB2 in the interleukin-1-induced activation of NFkappa B | journal = The Journal of Biological Chemistry | volume = 276 | issue = 45 | pages = 41661–41667 | date = November 2001 | pmid = 11518704 | doi = 10.1074/jbc.M102262200 | doi-access = free }}{{cite journal | vauthors = Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV | title = TRAF6 is a signal transducer for interleukin-1 | journal = Nature | volume = 383 | issue = 6599 | pages = 443–446 | date = October 1996 | pmid = 8837778 | doi = 10.1038/383443a0 | s2cid = 4269027 | bibcode = 1996Natur.383..443C }}{{cite journal | vauthors = Takatsuna H, Kato H, Gohda J, Akiyama T, Moriya A, Okamoto Y, Yamagata Y, Otsuka M, Umezawa K, Semba K, Inoue J | display-authors = 6 | title = Identification of TIFA as an adapter protein that links tumor necrosis factor receptor-associated factor 6 (TRAF6) to interleukin-1 (IL-1) receptor-associated kinase-1 (IRAK-1) in IL-1 receptor signaling | journal = The Journal of Biological Chemistry | volume = 278 | issue = 14 | pages = 12144–12150 | date = April 2003 | pmid = 12566447 | doi = 10.1074/jbc.M300720200 | doi-access = free }}{{cite journal | vauthors = Ling L, Goeddel DV | title = T6BP, a TRAF6-interacting protein involved in IL-1 signaling | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 17 | pages = 9567–9572 | date = August 2000 | pmid = 10920205 | pmc = 16905 | doi = 10.1073/pnas.170279097 | doi-access = free | bibcode = 2000PNAS...97.9567L }}{{cite journal | vauthors = Takaesu G, Ninomiya-Tsuji J, Kishida S, Li X, Stark GR, Matsumoto K | title = Interleukin-1 (IL-1) receptor-associated kinase leads to activation of TAK1 by inducing TAB2 translocation in the IL-1 signaling pathway | journal = Molecular and Cellular Biology | volume = 21 | issue = 7 | pages = 2475–2484 | date = April 2001 | pmid = 11259596 | pmc = 86880 | doi = 10.1128/MCB.21.7.2475-2484.2001 }}{{cite journal | vauthors = Chen F, Du Y, Zhang Z, Chen G, Zhang M, Shu HB, Zhai Z, Chen D | display-authors = 6 | title = Syntenin negatively regulates TRAF6-mediated IL-1R/TLR4 signaling | journal = Cellular Signalling | volume = 20 | issue = 4 | pages = 666–674 | date = April 2008 | pmid = 18234474 | doi = 10.1016/j.cellsig.2007.12.002 | s2cid = 28812149 }}
UBC,{{cite journal | vauthors = Newton K, Matsumoto ML, Wertz IE, Kirkpatrick DS, Lill JR, Tan J, Dugger D, Gordon N, Sidhu SS, Fellouse FA, Komuves L, French DM, Ferrando RE, Lam C, Compaan D, Yu C, Bosanac I, Hymowitz SG, Kelley RF, Dixit VM | display-authors = 6 | title = Ubiquitin chain editing revealed by polyubiquitin linkage-specific antibodies | journal = Cell | volume = 134 | issue = 4 | pages = 668–678 | date = August 2008 | pmid = 18724939 | doi = 10.1016/j.cell.2008.07.039 | doi-access = free }}{{cite journal | vauthors = Xiao H, Qian W, Staschke K, Qian Y, Cui G, Deng L, Ehsani M, Wang X, Qian YW, Chen ZJ, Gilmour R, Jiang Z, Li X | display-authors = 6 | title = Pellino 3b negatively regulates interleukin-1-induced TAK1-dependent NF kappaB activation | journal = The Journal of Biological Chemistry | volume = 283 | issue = 21 | pages = 14654–14664 | date = May 2008 | pmid = 18326498 | pmc = 2386918 | doi = 10.1074/jbc.M706931200 | doi-access = free }}
TOLLIP{{cite journal | vauthors = Burns K, Clatworthy J, Martin L, Martinon F, Plumpton C, Maschera B, Lewis A, Ray K, Tschopp J, Volpe F | display-authors = 6 | title = Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor | journal = Nature Cell Biology | volume = 2 | issue = 6 | pages = 346–351 | date = June 2000 | pmid = 10854325 | doi = 10.1038/35014038 | s2cid = 32036101 }}
TLR4{{cite journal | vauthors = He X, Jing Z, Cheng G | title = MicroRNAs: new regulators of Toll-like receptor signalling pathways | journal = BioMed Research International | volume = 2014 | pages = 945169 | year = 2014 | pmid = 24772440 | pmc = 3977468 | doi = 10.1155/2014/945169 | doi-access = free }}

Clinical significance

IRAK-1 signaling is involved in rheumatoid arthritis.{{cite web |title=IRAK1 gene |url=https://ghr.nlm.nih.gov/gene/IRAK1#conditions | archive-url = https://web.archive.org/web/20170220224820/https://ghr.nlm.nih.gov/gene/IRAK1 | archive-date = 20 February 2017 | website=Genetics Home Reference | publisher = U.S. National Library of Medicine }}{{cite journal | vauthors = Singer JW, Fleischman A, Al-Fayoumi S, Mascarenhas JO, Yu Q, Agarwal A | title = Inhibition of interleukin-1 receptor-associated kinase 1 (IRAK1) as a therapeutic strategy | journal = Oncotarget | volume = 9 | issue = 70 | pages = 33416–33439 | date = September 2018 | pmid = 30279971 | pmc = 6161786 | doi = 10.18632/oncotarget.26058 }} Moreover, IRAK-1 plays a significant role in cancer.