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'''Interleukin-1 receptor-associated kinase 1''' ('''IRAK-1)''' is an [[enzyme]] in humans encoded by the ''IRAK1'' [[gene]]<ref name="pmid9374458">{{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 = 1612–5 | date = November 1997 | pmid = 9374458 | doi = 10.1126/science.278.5343.1612 | bibcode = 1997Sci...278.1612M }}</ref><ref name="pmid8599092">{{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 = 1128–31 | date = February 1996 | pmid = 8599092 | doi = 10.1126/science.271.5252.1128 | bibcode = 1996Sci...271.1128C | s2cid = 42977425 }}</ref>. 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<ref>{{Cite journal |last=Jain |first=Ajay |last2=Kaczanowska |first2=Sabina |last3=Davila |first3=Eduardo |date=2014 |title=IL-1 Receptor-Associated Kinase Signaling and Its Role in Inflammation, Cancer Progression, and Therapy Resistance |url=https://www.frontiersin.org/article/10.3389/fimmu.2014.00553 |journal=Frontiers in Immunology |volume=5 |doi=10.3389/fimmu.2014.00553/full |issn=1664-3224}}</ref>. IRAK-1 is expressed in a variety of human immune cells types including [[Monocyte|monocytes]] and [[Macrophage|macrophages]]. Structurally, IRAK-1 contains an N-terminal death domain ([[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|MyD88]].
{{Infobox_gene}}
⚫
'''Interleukin-1 receptor-associated kinase 1''' is an [[enzyme]] that in humans is encoded by the ''IRAK1'' [[gene]].<ref name="pmid9374458">{{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 = 1612–5 | date = November 1997 | pmid = 9374458 | doi = 10.1126/science.278.5343.1612 | bibcode = 1997Sci...278.1612M }}</ref><ref name="pmid8599092">{{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 = 1128–31 | date = February 1996 | pmid = 8599092 | doi = 10.1126/science.271.5252.1128 | bibcode = 1996Sci...271.1128C | s2cid = 42977425 }}</ref>


== Function ==
== Function ==


This gene encodes the interleukin-1 receptor-associated kinase 1, one of two putative serine/threonine kinases that become associated with the [[Interleukin-1 receptor|interleukin-1 receptor (IL1R)]] upon stimulation. This gene is partially responsible for IL1-induced upregulation of the transcription factor [[NF-κB|NF-kappa B]]. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.<ref>{{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}}</ref>
IRAK-1 is classified as a enzyme, which regulates pathways in both innate and adaptive immune responses<ref>{{Cite web |title=IRAK1 - an overview {{!}} ScienceDirect Topics |url=https://www.sciencedirect.com/topics/immunology-and-microbiology/irak1 |access-date=2022-03-03 |website=www.sciencedirect.com}}</ref>. 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|interleukin-1 receptor (IL1R)]] upon stimulation. IRAK-1 is required for pro-inflammatory cytokine production downstream of TLR signaling pathways. nvolved in TLR and IL-1R signaling pathways. This gene is partially responsible for IL1-induced upregulation of the transcription factor [[NF-κB|NF-kappa B]]. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.<ref>{{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}}</ref>


[[Image:Toll-like receptor pathways revised.jpg|thumbnail|center|500px|Signaling pathway of toll-like receptors. Dashed grey lines represent unknown associations]]
[[Image:Toll-like receptor pathways revised.jpg|thumbnail|center|500px|Signaling pathway of toll-like receptors. Dashed grey lines represent unknown associations]]
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== Interactions ==
== Interactions ==


IRAK1 has been shown to [[Protein-protein interaction|interact]] with:
IRAK1 has been shown to [[Protein-protein interaction|interact]] with the following proteins:
{{div col|colwidth=20em}}
{{div col|colwidth=20em}}
* [[CHUK]]<ref name = pmid18180283/><ref name = pmid11096118/>
* [[CHUK]]<ref name = pmid18180283/><ref name = pmid11096118/>
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* [[TOLLIP]]<ref name="TschoppBurns2000">{{cite journal | vauthors = Burns K, Clatworthy J, Martin L, Martinon F, Plumpton C, Maschera B, Lewis A, Ray K, Tschopp J, Volpe F | 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 = 346–51 | date = June 2000 | pmid = 10854325 | doi = 10.1038/35014038 | s2cid = 32036101 }}</ref>
* [[TOLLIP]]<ref name="TschoppBurns2000">{{cite journal | vauthors = Burns K, Clatworthy J, Martin L, Martinon F, Plumpton C, Maschera B, Lewis A, Ray K, Tschopp J, Volpe F | 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 = 346–51 | date = June 2000 | pmid = 10854325 | doi = 10.1038/35014038 | s2cid = 32036101 }}</ref>
* [[TLR4]]<ref name="HeJing2014">{{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 = 1–14 | year = 2014 | pmid = 24772440 | doi = 10.1155/2014/945169 | pmc=3977468| doi-access = free }}</ref>
* [[TLR4]]<ref name="HeJing2014">{{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 = 1–14 | year = 2014 | pmid = 24772440 | doi = 10.1155/2014/945169 | pmc=3977468| doi-access = free }}</ref>
{{Div col end}}
{{Div col end}}IRAK1




== Clinical significance ==
== Clinical significance ==

Revision as of 04:24, 3 March 2022

Interleukin-1 receptor-associated kinase 1 (IRAK-1) is an enzyme in humans encoded by the IRAK1 gene[1][2]. 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[3]. IRAK-1 is expressed in a variety of human immune cells types including monocytes and macrophages. Structurally, 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.

Function

IRAK-1 is classified as a enzyme, which regulates pathways in both innate and adaptive immune responses[4]. 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 signaling pathways. nvolved in TLR and IL-1R signaling pathways. This gene is partially responsible for IL1-induced upregulation of the transcription factor NF-kappa B. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[5]

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

Interactions

IRAK1 has been shown to interact with the following proteins:

IRAK1


Clinical significance

IRAK1 signaling is involved in rheumatoid arthritis.[25][26]

References

  1. ^ Muzio M, Ni J, Feng P, Dixit VM (November 1997). "IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling". Science. 278 (5343): 1612–5. Bibcode:1997Sci...278.1612M. doi:10.1126/science.278.5343.1612. PMID 9374458.
  2. ^ Cao Z, Henzel WJ, Gao X (February 1996). "IRAK: a kinase associated with the interleukin-1 receptor". Science. 271 (5252): 1128–31. Bibcode:1996Sci...271.1128C. doi:10.1126/science.271.5252.1128. PMID 8599092. S2CID 42977425.
  3. ^ Jain, Ajay; Kaczanowska, Sabina; Davila, Eduardo (2014). "IL-1 Receptor-Associated Kinase Signaling and Its Role in Inflammation, Cancer Progression, and Therapy Resistance". Frontiers in Immunology. 5. doi:10.3389/fimmu.2014.00553/full. ISSN 1664-3224.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  4. ^ "IRAK1 - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2022-03-03.
  5. ^ "Entrez Gene: IRAK1 interleukin-1 receptor-associated kinase 1".
  6. ^ a b c d Windheim M, Stafford M, Peggie M, Cohen P (March 2008). "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". Molecular and Cellular Biology. 28 (5): 1783–91. doi:10.1128/MCB.02380-06. PMC 2258775. PMID 18180283.
  7. ^ a b Vig E, Green M, Liu Y, Yu KY, Kwon HJ, Tian J, Goebl MG, Harrington MA (March 2001). "SIMPL is a tumor necrosis factor-specific regulator of nuclear factor-kappaB activity". The Journal of Biological Chemistry. 276 (11): 7859–66. doi:10.1074/jbc.M010399200. PMID 11096118.
  8. ^ a b Conze DB, Wu CJ, Thomas JA, Landstrom A, Ashwell JD (May 2008). "Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activation". Molecular and Cellular Biology. 28 (10): 3538–47. doi:10.1128/MCB.02098-07. PMC 2423148. PMID 18347055.
  9. ^ Chen BC, Wu WT, Ho FM, Lin WW (July 2002). "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". The Journal of Biological Chemistry. 277 (27): 24169–79. doi:10.1074/jbc.M106014200. PMID 11976320.
  10. ^ a b 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): 19403–10. doi:10.1074/jbc.274.27.19403. PMID 10383454.
  11. ^ a b Li S, Strelow A, Fontana EJ, Wesche H (April 2002). "IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase". Proceedings of the National Academy of Sciences of the United States of America. 99 (8): 5567–72. Bibcode:2002PNAS...99.5567L. doi:10.1073/pnas.082100399. PMC 122810. PMID 11960013.
  12. ^ 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 (September 2001). "Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction". Nature. 413 (6851): 78–83. Bibcode:2001Natur.413...78F. doi:10.1038/35092578. PMID 11544529. S2CID 4333764.
  13. ^ a b c Database, GeneCards Human Gene. "IRAK1 Gene - GeneCards | IRAK1 Protein | IRAK1 Antibody". www.genecards.org.
  14. ^ Muzio, M. (1997). "IRAK (Pelle) Family Member IRAK-2 and MyD88 as Proximal Mediators of IL-1 Signaling". Science. 278 (5343): 1612–1615. Bibcode:1997Sci...278.1612M. doi:10.1126/science.278.5343.1612. ISSN 0036-8075. PMID 9374458.
  15. ^ 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): 41661–7. doi:10.1074/jbc.M102262200. PMID 11518704.
  16. ^ Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV (October 1996). "TRAF6 is a signal transducer for interleukin-1". Nature. 383 (6599): 443–6. Bibcode:1996Natur.383..443C. doi:10.1038/383443a0. PMID 8837778. S2CID 4269027.
  17. ^ Takatsuna H, Kato H, Gohda J, Akiyama T, Moriya A, Okamoto Y, Yamagata Y, Otsuka M, Umezawa K, Semba K, Inoue J (April 2003). "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". The Journal of Biological Chemistry. 278 (14): 12144–50. doi:10.1074/jbc.M300720200. PMID 12566447.
  18. ^ Ling L, Goeddel DV (August 2000). "T6BP, a TRAF6-interacting protein involved in IL-1 signaling". Proceedings of the National Academy of Sciences of the United States of America. 97 (17): 9567–72. Bibcode:2000PNAS...97.9567L. doi:10.1073/pnas.170279097. PMC 16905. PMID 10920205.
  19. ^ Takaesu G, Ninomiya-Tsuji J, Kishida S, Li X, Stark GR, Matsumoto K (April 2001). "Interleukin-1 (IL-1) receptor-associated kinase leads to activation of TAK1 by inducing TAB2 translocation in the IL-1 signaling pathway". Molecular and Cellular Biology. 21 (7): 2475–84. doi:10.1128/MCB.21.7.2475-2484.2001. PMC 86880. PMID 11259596.
  20. ^ Chen F, Du Y, Zhang Z, Chen G, Zhang M, Shu HB, Zhai Z, Chen D (April 2008). "Syntenin negatively regulates TRAF6-mediated IL-1R/TLR4 signaling". Cellular Signalling. 20 (4): 666–74. doi:10.1016/j.cellsig.2007.12.002. PMID 18234474.
  21. ^ 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 (August 2008). "Ubiquitin chain editing revealed by polyubiquitin linkage-specific antibodies". Cell. 134 (4): 668–78. doi:10.1016/j.cell.2008.07.039. PMID 18724939.
  22. ^ 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 (May 2008). "Pellino 3b negatively regulates interleukin-1-induced TAK1-dependent NF kappaB activation". The Journal of Biological Chemistry. 283 (21): 14654–64. doi:10.1074/jbc.M706931200. PMC 2386918. PMID 18326498.
  23. ^ Burns K, Clatworthy J, Martin L, Martinon F, Plumpton C, Maschera B, Lewis A, Ray K, Tschopp J, Volpe F (June 2000). "Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor". Nature Cell Biology. 2 (6): 346–51. doi:10.1038/35014038. PMID 10854325. S2CID 32036101.
  24. ^ He X, Jing Z, Cheng G (2014). "MicroRNAs: new regulators of Toll-like receptor signalling pathways". BioMed Research International. 2014: 1–14. doi:10.1155/2014/945169. PMC 3977468. PMID 24772440.
  25. ^ Reference, Genetics Home. "IRAK1 gene". Genetics Home Reference.
  26. ^ Singer JW, Fleischman A, Al-Fayoumi S, Mascarenhas JO, Yu Q, Agarwal A (September 2018). "Inhibition of interleukin-1 receptor-associated kinase 1 (IRAK1) as a therapeutic strategy". Oncotarget. 9 (70): 33416–33439. doi:10.18632/oncotarget.26058. PMC 6161786. PMID 30279971.

Further reading

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