9kv7

Structural highlights

Function

RIPK1_MOUSE Serine-threonine kinase which is a key regulator of TNF-mediated apoptosis, necroptosis and inflammatory pathways (PubMed:24557836, PubMed:24813849, PubMed:24813850, PubMed:27819681, PubMed:28842570, PubMed:31511692, PubMed:31827280, PubMed:31827281, PubMed:33397971). Exhibits kinase activity-dependent functions that regulate cell death and kinase-independent scaffold functions regulating inflammatory signaling and cell survival (PubMed:24557836, PubMed:24813849, PubMed:24813850, PubMed:28842570, PubMed:31519886, PubMed:31519887). Has kinase-independent scaffold functions: upon binding of TNF to TNFR1, RIPK1 is recruited to the TNF-R1 signaling complex (TNF-RSC also known as complex I) where it acts as a scaffold protein promoting cell survival, in part, by activating the canonical NF-kappa-B pathway (PubMed:31519886, PubMed:31519887). Kinase activity is essential to regulate necroptosis and apoptosis, two parallel forms of cell death: upon activation of its protein kinase activity, regulates assembly of two death-inducing complexes, namely complex IIa (RIPK1-FADD-CASP8), which drives apoptosis, and the complex IIb (RIPK1-RIPK3-MLKL), which drives necroptosis (PubMed:27819681, PubMed:27819682, PubMed:28842570, PubMed:29440439, PubMed:30988283, PubMed:31519886, PubMed:31519887). RIPK1 is required to limit CASP8-dependent TNFR1-induced apoptosis (PubMed:24557836, PubMed:24813849, PubMed:24813850). In normal conditions, RIPK1 acts as an inhibitor of RIPK3-dependent necroptosis, a process mediated by RIPK3 component of complex IIb, which catalyzes phosphorylation of MLKL upon induction by ZBP1 (PubMed:24557836, PubMed:27819681, PubMed:27819682, PubMed:31358656). Inhibits RIPK3-mediated necroptosis via FADD-mediated recruitment of CASP8, which cleaves RIPK1 and limits TNF-induced necroptosis (PubMed:31358656). Required to inhibit apoptosis and necroptosis during embryonic development: acts by preventing the interaction of TRADD with FADD thereby limiting aberrant activation of CASP8 (PubMed:30185824, PubMed:30867408). In addition to apoptosis and necroptosis, also involved in inflammatory response by promoting transcriptional production of pro-inflammatory cytokines, such as interleukin-6 (IL6) (PubMed:31827280, PubMed:31827281). Phosphorylates RIPK3: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation (By similarity). Phosphorylates DAB2IP at 'Ser-728' in a TNF-alpha-dependent manner, and thereby activates the MAP3K5-JNK apoptotic cascade (By similarity). Required for ZBP1-induced NF-kappa-B activation in response to DNA damage (PubMed:12654725, PubMed:19590578).[UniProtKB:Q13546]^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19]}

References

1. ↑ Hur GM, Lewis J, Yang Q, Lin Y, Nakano H, Nedospasov S, Liu ZG. The death domain kinase RIP has an essential role in DNA damage-induced NF-kappa B activation. Genes Dev. 2003 Apr 1;17(7):873-82. PMID:12654725 doi:10.1101/gad.1062403
2. ↑ Rebsamen M, Heinz LX, Meylan E, Michallet MC, Schroder K, Hofmann K, Vazquez J, Benedict CA, Tschopp J. DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-kappaB. EMBO Rep. 2009 Aug;10(8):916-22. doi: 10.1038/embor.2009.109. Epub 2009 Jul 10. PMID:19590578 doi:http://dx.doi.org/10.1038/embor.2009.109
3. ↑ Newton K, Dugger DL, Wickliffe KE, Kapoor N, de Almagro MC, Vucic D, Komuves L, Ferrando RE, French DM, Webster J, Roose-Girma M, Warming S, Dixit VM. Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science. 2014 Mar 21;343(6177):1357-60. PMID:24557836 doi:10.1126/science.1249361
4. ↑ Rickard JA, O'Donnell JA, Evans JM, Lalaoui N, Poh AR, Rogers T, Vince JE, Lawlor KE, Ninnis RL, Anderton H, Hall C, Spall SK, Phesse TJ, Abud HE, Cengia LH, Corbin J, Mifsud S, Di Rago L, Metcalf D, Ernst M, Dewson G, Roberts AW, Alexander WS, Murphy JM, Ekert PG, Masters SL, Vaux DL, Croker BA, Gerlic M, Silke J. RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell. 2014 May 22;157(5):1175-88. PMID:24813849 doi:10.1016/j.cell.2014.04.019
5. ↑ Dillon CP, Weinlich R, Rodriguez DA, Cripps JG, Quarato G, Gurung P, Verbist KC, Brewer TL, Llambi F, Gong YN, Janke LJ, Kelliher MA, Kanneganti TD, Green DR. RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. Cell. 2014 May 22;157(5):1189-202. PMID:24813850 doi:10.1016/j.cell.2014.04.018
6. ↑ Lin J, Kumari S, Kim C, Van TM, Wachsmuth L, Polykratis A, Pasparakis M. RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation. Nature. 2016 Dec 1;540(7631):124-128. PMID:27819681 doi:10.1038/nature20558
7. ↑ Newton K, Wickliffe KE, Maltzman A, Dugger DL, Strasser A, Pham VC, Lill JR, Roose-Girma M, Warming S, Solon M, Ngu H, Webster JD, Dixit VM. RIPK1 inhibits ZBP1-driven necroptosis during development. Nature. 2016 Dec 1;540(7631):129-133. PMID:27819682 doi:10.1038/nature20559
8. ↑ Geng J, Ito Y, Shi L, Amin P, Chu J, Ouchida AT, Mookhtiar AK, Zhao H, Xu D, Shan B, Najafov A, Gao G, Akira S, Yuan J. Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis. Nat Commun. 2017 Aug 25;8(1):359. PMID:28842570 doi:10.1038/s41467-017-00406-w
9. ↑ Meng H, Liu Z, Li X, Wang H, Jin T, Wu G, Shan B, Christofferson DE, Qi C, Yu Q, Li Y, Yuan J. Death-domain dimerization-mediated activation of RIPK1 controls necroptosis and RIPK1-dependent apoptosis. Proc Natl Acad Sci U S A. 2018 Feb 27;115(9):E2001-E2009. PMID:29440439 doi:10.1073/pnas.1722013115
10. ↑ Anderton H, Bandala-Sanchez E, Simpson DS, Rickard JA, Ng AP, Di Rago L, Hall C, Vince JE, Silke J, Liccardi G, Feltham R. RIPK1 prevents TRADD-driven, but TNFR1 independent, apoptosis during development. Cell Death Differ. 2019 May;26(5):877-889. PMID:30185824 doi:10.1038/s41418-018-0166-8
11. ↑ Zhang X, Dowling JP, Zhang J. RIPK1 can mediate apoptosis in addition to necroptosis during embryonic development. Cell Death Dis. 2019 Mar 13;10(3):245. PMID:30867408 doi:10.1038/s41419-019-1490-8
12. ↑ Dondelinger Y, Delanghe T, Priem D, Wynosky-Dolfi MA, Sorobetea D, Rojas-Rivera D, Giansanti P, Roelandt R, Gropengiesser J, Ruckdeschel K, Savvides SN, Heck AJR, Vandenabeele P, Brodsky IE, Bertrand MJM. Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation. Nat Commun. 2019 Apr 15;10(1):1729. PMID:30988283 doi:10.1038/s41467-019-09690-0
13. ↑ Ingram JP, Thapa RJ, Fisher A, Tummers B, Zhang T, Yin C, Rodriguez DA, Guo H, Lane R, Williams R, Slifker MJ, Basagoudanavar SH, Rall GF, Dillon CP, Green DR, Kaiser WJ, Balachandran S. ZBP1/DAI Drives RIPK3-Mediated Cell Death Induced by IFNs in the Absence of RIPK1. J Immunol. 2019 Sep 1;203(5):1348-1355. PMID:31358656 doi:10.4049/jimmunol.1900216
14. ↑ Newton K, Wickliffe KE, Dugger DL, Maltzman A, Roose-Girma M, Dohse M, Kőműves L, Webster JD, Dixit VM. Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis. Nature. 2019 Oct;574(7778):428-431. PMID:31511692 doi:10.1038/s41586-019-1548-x
15. ↑ Zhang X, Zhang H, Xu C, Li X, Li M, Wu X, Pu W, Zhou B, Wang H, Li D, Ding Q, Ying H, Wang H, Zhang H. Ubiquitination of RIPK1 suppresses programmed cell death by regulating RIPK1 kinase activation during embryogenesis. Nat Commun. 2019 Sep 13;10(1):4158. PMID:31519886 doi:10.1038/s41467-019-11839-w
16. ↑ Tang Y, Tu H, Zhang J, Zhao X, Wang Y, Qin J, Lin X. K63-linked ubiquitination regulates RIPK1 kinase activity to prevent cell death during embryogenesis and inflammation. Nat Commun. 2019 Sep 13;10(1):4157. PMID:31519887 doi:10.1038/s41467-019-12033-8
17. ↑ Tao P, Sun J, Wu Z, Wang S, Wang J, Li W, Pan H, Bai R, Zhang J, Wang Y, Lee PY, Ying W, Zhou Q, Hou J, Wang W, Sun B, Yang M, Liu D, Fang R, Han H, Yang Z, Huang X, Li H, Deuitch N, Zhang Y, Dissanayake D, Haude K, McWalter K, Roadhouse C, MacKenzie JJ, Laxer RM, Aksentijevich I, Yu X, Wang X, Yuan J, Zhou Q. A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1. Nature. 2020 Jan;577(7788):109-114. PMID:31827280 doi:10.1038/s41586-019-1830-y
18. ↑ Lalaoui N, Boyden SE, Oda H, Wood GM, Stone DL, Chau D, Liu L, Stoffels M, Kratina T, Lawlor KE, Zaal KJM, Hoffmann PM, Etemadi N, Shield-Artin K, Biben C, Tsai WL, Blake MD, Kuehn HS, Yang D, Anderton H, Silke N, Wachsmuth L, Zheng L, Moura NS, Beck DB, Gutierrez-Cruz G, Ombrello AK, Pinto-Patarroyo GP, Kueh AJ, Herold MJ, Hall C, Wang H, Chae JJ, Dmitrieva NI, McKenzie M, Light A, Barham BK, Jones A, Romeo TM, Zhou Q, Aksentijevich I, Mullikin JC, Gross AJ, Shum AK, Hawkins ED, Masters SL, Lenardo MJ, Boehm M, Rosenzweig SD, Pasparakis M, Voss AK, Gadina M, Kastner DL, Silke J. Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease. Nature. 2020 Jan;577(7788):103-108. PMID:31827281 doi:10.1038/s41586-019-1828-5
19. ↑ Muendlein HI, Connolly WM, Magri Z, Smirnova I, Ilyukha V, Gautam A, Degterev A, Poltorak A. ZBP1 promotes LPS-induced cell death and IL-1β release via RHIM-mediated interactions with RIPK1. Nat Commun. 2021 Jan 4;12(1):86. PMID:33397971 doi:10.1038/s41467-020-20357-z
20. ↑ Chen Z, Gu X, Chen H, Zhang H, Liu J, Yang X, Cai Y, Zhang M, Yan L, Yang Y, Shan B, Zhu ZJ, Zhang Y, Gu J, Xu D. RIPK1 senses S-adenosylmethionine scarcity to drive cell death and inflammation. Cell Metab. 2025 Aug 5;37(8):1732-1749.e9. PMID:40570842 doi:10.1016/j.cmet.2025.05.014