Receptor-interacting serine/threonine-protein kinase 3 is an enzyme that is encoded by the RIPK3gene in humans.[5][6][7][8]
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.[7] Interactions between RIPK1 and RIPK3 also form a necrosome, which triggers apoptosis.[9]
The red highlighted region of RIPK3 represents the Protein Kinase domain. The cyan region highlights the RIP homotypic interaction motif (RHIM) motif.[10]
Interactions
RIPK3 has been shown to interact with RIPK1 to form an amyloid spine[5][8] The RIP Homotypic Interaction Motifs (RHIM) of RIPK3 allows it to form a necrosome with RIPK1.[9] This interaction makes heterotypic β sheets, which bind together to form an alternating “ladder” of Serine from RIPK1 and Cysteine from RIPK3.[9]
Clinical significance
RIPK3 is believed to contribute to lung inflammation and injury during severe infections with the influenza A virus. The experimental RIPK3 inhibitor UH15-38 has shown potential in preclinical studies to reduce mortality and lung damage in mice infected with influenza, indicating that RIPK3 may serve as a therapeutic target for managing hyper-inflammatory conditions such as influenza-related acute respiratory distress syndrome (ARDS).[11][12]
Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, et al. (February 2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nature Cell Biology. 6 (2): 97–105. doi:10.1038/ncb1086. PMID14743216. S2CID11683986.
Yang Y, Hu W, Feng S, Ma J, Wu M (June 2005). "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. doi:10.1016/j.bbrc.2005.04.114. PMID15896315.
Zhao L, Wang G, Lu D, Wu J, Song F, Dong J, et al. (June 2006). "Homocysteine, hRIP3 and congenital cardiovascular malformations". Anatomy and Embryology. 211 (3): 203–212. doi:10.1007/s00429-005-0074-9. PMID16429275. S2CID7176317.
Feng S, Ma L, Yang Y, Wu M (September 2006). "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. doi:10.1016/j.bbrc.2006.06.118. PMID16844082.
