RIPK3 explained

Receptor-interacting serine/threonine-protein kinase 3 is an enzyme that is encoded by the RIPK3 gene in humans.^{[1] [2] [3] [4]}

The product of this gene is a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases. It contains a C-terminal domain unique from other RIP family members. The encoded protein is predominantly localized to the cytoplasm, and can undergo nucleocytoplasmic shuttling dependent on novel nuclear localization and export signals. It is a component of the tumor necrosis factor (TNF) receptor-I signaling complex, and can induce necroptosis by interaction with RIPK1 and MLKL in a protein complex termed the necrosome. Interactions between RIPK1 and RIPK3 also form a necrosome, which triggers apoptosis.^[5]

Interactions

RIPK3 has been shown to interact with RIPK1 to form an amyloid spine The RIP Homotypic Interaction Motifs (RHIM) of RIPK3 allows it to form a necrosome with RIPK1. This interaction makes heterotypic β sheets, which bind together to form an alternating “ladder” of Serine from RIPK1 and Cysteine from RIPK3.

Further reading

• Kasof GM, Prosser JC, Liu D, Lorenzi MV, Gomes BC . The RIP-like kinase, RIP3, induces apoptosis and NF-kappaB nuclear translocation and localizes to mitochondria . FEBS Letters . 473 . 3 . 285–291 . May 2000 . 10818227 . 10.1016/S0014-5793(00)01473-3 . free .
• Sun X, Yin J, Starovasnik MA, Fairbrother WJ, Dixit VM . Identification of a novel homotypic interaction motif required for the phosphorylation of receptor-interacting protein (RIP) by RIP3 . The Journal of Biological Chemistry . 277 . 11 . 9505–9511 . March 2002 . 11734559 . 10.1074/jbc.M109488200 . free .
• Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proceedings of the National Academy of Sciences of the United States of America . 99 . 26 . 16899–16903 . December 2002 . 12477932 . 139241 . 10.1073/pnas.242603899 . 2002PNAS...9916899M . free .
• Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G . A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway . Nature Cell Biology . 6 . 2 . 97–105 . February 2004 . 14743216 . 10.1038/ncb1086 . 11683986 .
• Meylan E, Burns K, Hofmann K, Blancheteau V, Martinon F, Kelliher M, Tschopp J . RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation . Nature Immunology . 5 . 5 . 503–507 . May 2004 . 15064760 . 10.1038/ni1061 . 12570157 .
• Yang Y, Ma J, Chen Y, Wu M . Nucleocytoplasmic shuttling of receptor-interacting protein 3 (RIP3): identification of novel nuclear export and import signals in RIP3 . The Journal of Biological Chemistry . 279 . 37 . 38820–38829 . September 2004 . 15208320 . 10.1074/jbc.M401663200 . free .
• Yang Y, Hu W, Feng S, Ma J, Wu M . RIP3 beta and RIP3 gamma, two novel splice variants of receptor-interacting protein 3 (RIP3), downregulate RIP3-induced apoptosis . Biochemical and Biophysical Research Communications . 332 . 1 . 181–187 . June 2005 . 15896315 . 10.1016/j.bbrc.2005.04.114 .
• Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S . Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes . Genome Research . 16 . 1 . 55–65 . January 2006 . 16344560 . 1356129 . 10.1101/gr.4039406 .
• Zhao L, Wang G, Lu D, Wu J, Song F, Dong J, Bi Z, Li Y . Homocysteine, hRIP3 and congenital cardiovascular malformations . Anatomy and Embryology . 211 . 3 . 203–212 . June 2006 . 16429275 . 10.1007/s00429-005-0074-9 . 7176317 .
• Feng S, Ma L, Yang Y, Wu M . Truncated RIP3 (tRIP3) acts upstream of FADD to induce apoptosis in the human hepatocellular carcinoma cell line QGY-7703 . Biochemical and Biophysical Research Communications . 347 . 3 . 558–565 . September 2006 . 16844082 . 10.1016/j.bbrc.2006.06.118 .
• Ahn KS, Sethi G, Krishnan K, Aggarwal BB . Gamma-tocotrienol inhibits nuclear factor-kappaB signaling pathway through inhibition of receptor-interacting protein and TAK1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis . The Journal of Biological Chemistry . 282 . 1 . 809–820 . January 2007 . 17114179 . 10.1074/jbc.M610028200 . free .

Notes and References

1. Yu PW, Huang BC, Shen M, Quast J, Chan E, Xu X, Nolan GP, Payan DG, Luo Y . Identification of RIP3, a RIP-like kinase that activates apoptosis and NFkappaB . Current Biology . 9 . 10 . 539–542 . May 1999 . 10339433 . 10.1016/S0960-9822(99)80239-5 . free . 1999CBio....9..539Y .
2. Sun X, Lee J, Navas T, Baldwin DT, Stewart TA, Dixit VM . RIP3, a novel apoptosis-inducing kinase . The Journal of Biological Chemistry . 274 . 24 . 16871–16875 . June 1999 . 10358032 . 10.1074/jbc.274.24.16871 . free .
3. Web site: Entrez Gene: RIPK3 receptor-interacting serine-threonine kinase 3.
4. Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki K, Hsiao YS, Damko E, Moquin D, Walz T, McDermott A, Chan FK, Wu H . The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis . Cell . 150 . 2 . 339–350 . July 2012 . 22817896 . 3664196 . 10.1016/j.cell.2012.06.019 .
5. Mompeán M, Li W, Li J, Laage S, Siemer AB, Bozkurt G, Wu H, McDermott AE . The Structure of the Necrosome RIPK1-RIPK3 Core, a Human Hetero-Amyloid Signaling Complex . Cell . 173 . 5 . 1244–1253.e10 . May 2018 . 29681455 . 10.1016/j.cell.2018.03.032 . 6002806 .