RIPK3

RIPK3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4M66, 4M69
Identifiers
Aliases	RIPK3 , RIP3, receptor interacting serine/threonine kinase 3
External IDs	OMIM: 605817; MGI: 2154952; HomoloGene: 31410; GeneCards: RIPK3; OMA:RIPK3 - orthologs
Gene location (Human) Chr. Chromosome 14 (human) [1] Band 14q12 Start 24,336,025 bp [1] End 24,340,022 bp [1]
Gene location (Mouse) Chr. Chromosome 14 (mouse) [2] Band 14|14 C3 Start 56,022,452 bp [2] End 56,026,322 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in granulocyte mucosa of transverse colon blood duodenum spleen rectum appendix monocyte right lobe of thyroid gland lymph node Top expressed in endothelial cell of lymphatic vessel yolk sac thymus Paneth cell internal carotid artery cartilage organ dermis epithelium of small intestine external carotid artery embryo More reference expression data BioGPS n/a
Gene ontology Molecular function transferase activity protein kinase activity nucleotide binding transcription coactivator activity kinase activity protein serine/threonine kinase activity NF-kappaB-inducing kinase activity protein binding identical protein binding ATP binding protein-containing complex binding Cellular component cytoplasm cytosol membrane plasma membrane intracellular anatomical structure mitochondrion Biological process regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation amyloid fibril formation T cell differentiation in thymus protein heterooligomerization phosphorylation thymus development regulation of interferon-gamma production positive regulation of oxidoreductase activity regulation of adaptive immune response spleen development regulation of reactive oxygen species metabolic process regulation of activation-induced cell death of T cells T cell homeostasis positive regulation of phosphatase activity positive regulation of necroptotic process protein phosphorylation regulation of activated T cell proliferation positive regulation of reactive oxygen species metabolic process NIK/NF-kappaB signaling positive regulation of NF-kappaB transcription factor activity apoptotic signaling pathway protein autophosphorylation positive regulation of ligase activity necroptosis regulation of T cell mediated cytotoxicity I-kappaB kinase/NF-kappaB signaling lymph node development protein homooligomerization activation of protein kinase activity positive regulation of intrinsic apoptotic signaling pathway signal transduction programmed cell death positive regulation of necrotic cell death positive regulation of nucleic acid-templated transcription cellular response to hydrogen peroxide programmed necrotic cell death Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 11035 56532 Ensembl ENSG00000129465 ENSG00000285379 ENSMUSG00000022221 UniProt Q9Y572 Q9QZL0 RefSeq (mRNA) NM_006871 NM_001164107 NM_001164108 NM_019955 RefSeq (protein) NP_006862 NP_001157579 NP_001157580 NP_064339 Location (UCSC) Chr 14: 24.34 – 24.34 Mb Chr 14: 56.02 – 56.03 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Receptor-interacting serine/threonine-protein kinase 3 is an enzyme that is encoded by the RIPK3 gene 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.

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] [13]}

References

1. ENSG00000285379 GRCh38: Ensembl release 89: ENSG00000129465, ENSG00000285379 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000022221 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Yu PW, Huang BC, Shen M, Quast J, Chan E, Xu X, et al. (May 1999). "Identification of RIP3, a RIP-like kinase that activates apoptosis and NFkappaB". Current Biology. 9 (10): 539–542. Bibcode:1999CBio....9..539Y. doi: 10.1016/S0960-9822(99)80239-5 . PMID   10339433.
6. Sun X, Lee J, Navas T, Baldwin DT, Stewart TA, Dixit VM (June 1999). "RIP3, a novel apoptosis-inducing kinase". The Journal of Biological Chemistry. 274 (24): 16871–16875. doi: 10.1074/jbc.274.24.16871 . PMID   10358032.
7. "Entrez Gene: RIPK3 receptor-interacting serine-threonine kinase 3".
8. Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki K, Hsiao YS, et al. (July 2012). "The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis". Cell. 150 (2): 339–350. doi:10.1016/j.cell.2012.06.019. PMC   3664196 . PMID   22817896.
9. Mompeán M, Li W, Li J, Laage S, Siemer AB, Bozkurt G, et al. (May 2018). "The Structure of the Necrosome RIPK1-RIPK3 Core, a Human Hetero-Amyloid Signaling Complex". Cell. 173 (5): 1244–1253.e10. doi:10.1016/j.cell.2018.03.032. PMC   6002806 . PMID   29681455.
10. "RIPK3 - Receptor-interacting serine/threonine-protein kinase 3 - Homo sapiens (Human) - RIPK3 gene & protein". www.uniprot.org. Retrieved 2022-05-13.
11. Cao X, Tan J, Zheng R, Wang F, Zhou L, Yi J, et al. (28 August 2024). "Targeting necroptosis: a promising avenue for respiratory disease treatment". Cell Communication and Signaling. 22 (1): 418. doi: 10.1186/s12964-024-01804-6 . ISSN   1478-811X. PMC   11350980 . PMID   39192326.
12. Gautam A, Boyd DF, Nikhar S, Zhang T, Siokas I, Van de Velde LA, et al. (April 2024). "Necroptosis blockade prevents lung injury in severe influenza". Nature. 628 (8009): 835–843. doi:10.1038/s41586-024-07265-8. PMC  11151938. PMID   38600381.
13. Halford B (10 April 2024). "Compound prevents flu-related lung damage in mice". Chemical & Engineering News. Retrieved 5 November 2024.

Further reading

• Kasof GM, Prosser JC, Liu D, Lorenzi MV, Gomes BC (May 2000). "The RIP-like kinase, RIP3, induces apoptosis and NF-kappaB nuclear translocation and localizes to mitochondria". FEBS Letters. 473 (3): 285–291. doi: 10.1016/S0014-5793(00)01473-3 . PMID   10818227.
• Sun X, Yin J, Starovasnik MA, Fairbrother WJ, Dixit VM (March 2002). "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. doi: 10.1074/jbc.M109488200 . PMID   11734559.
• Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, et al. (December 2002). "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. Bibcode:2002PNAS...9916899M. doi: 10.1073/pnas.242603899 . PMC   139241 . PMID   12477932.
• 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. PMID   14743216. S2CID   11683986.
• Meylan E, Burns K, Hofmann K, Blancheteau V, Martinon F, Kelliher M, et al. (May 2004). "RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation" (PDF). Nature Immunology. 5 (5): 503–507. doi:10.1038/ni1061. PMID   15064760. S2CID   12570157.
• Yang Y, Ma J, Chen Y, Wu M (September 2004). "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. doi: 10.1074/jbc.M401663200 . PMID   15208320.
• 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. PMID   15896315.
• Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, et al. (January 2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC   1356129 . PMID   16344560.
• 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. PMID   16429275. S2CID   7176317.
• 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. PMID   16844082.
• Ahn KS, Sethi G, Krishnan K, Aggarwal BB (January 2007). "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. doi: 10.1074/jbc.M610028200 . PMID   17114179.