PMID- 23612963 OWN - NLM STAT- MEDLINE DCOM- 20130812 LR - 20211021 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 288 IP - 23 DP - 2013 Jun 7 TI - Diverse sequence determinants control human and mouse receptor interacting protein 3 (RIP3) and mixed lineage kinase domain-like (MLKL) interaction in necroptotic signaling. PG - 16247-16261 LID - S0021-9258(20)53637-5 [pii] LID - 10.1074/jbc.M112.435545 [doi] AB - Receptor interacting protein 3 (RIP3) is a protein kinase essential for TNF-induced necroptosis. Phosphorylation on Ser-227 in human RIP3 (hRIP3) is required for its interaction with human mixed lineage kinase domain-like (MLKL) in the necrosome, a signaling complex induced by TNF stimulation. RIP1 and RIP3 mediate necrosome aggregation leading to the formation of amyloid-like signaling complexes. We found that TNF induces Thr-231 and Ser-232 phosphorylation in mouse RIP3 (mRIP3) and this phosphorylation is required for mRIP3 to interact with mMLKL. Ser-232 in mRIP3 corresponds to Ser-227 in hRIP3, whereas Thr-231 is not conserved in hRIP3. Although the RIP3-MLKL interaction is required for necroptosis in both human and mouse cells, hRIP3 does not interact with mMLKL and mRIP3 cannot bind to hMLKL. The species specificity of the RIP3-MLKL interaction is primarily determined by the sequence differences in the phosphorylation sites and the flanking sequence around the phosphorylation sites in hRIP3 and mRIP3. It appears that the RIP3-MLKL interaction has been selected as an evolutionarily conserved mechanism in mediating necroptosis signaling despite that differing structural and mechanistic bases for this interaction emerged simultaneously in different organisms. In addition, we further revealed that the interaction of RIP3 with MLKL prevented massive abnormal RIP3 aggregation, and therefore should be crucial for formation of the amyloid signaling complex of necrosomes. We also found that the interaction between RIP3 and MLKL is required for the translocation of necrosomes to mitochondria-associated membranes. Our data demonstrate the importance of the RIP3-MLKL interaction in the formation of functional necrosomes and suggest that translocation of necrosomes to mitochondria-associated membranes is essential for necroptosis signaling. FAU - Chen, Wanze AU - Chen W AD - State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, Fujian 361005. FAU - Zhou, Zhenru AU - Zhou Z AD - State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, Fujian 361005. FAU - Li, Lisheng AU - Li L AD - State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, Fujian 361005. FAU - Zhong, Chuan-Qi AU - Zhong CQ AD - State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, Fujian 361005. FAU - Zheng, Xinru AU - Zheng X AD - State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, Fujian 361005. FAU - Wu, Xiurong AU - Wu X AD - State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, Fujian 361005. FAU - Zhang, Yingying AU - Zhang Y AD - State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, Fujian 361005. FAU - Ma, Huan AU - Ma H AD - State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, Fujian 361005. FAU - Huang, Deli AU - Huang D AD - State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, Fujian 361005. FAU - Li, Wenjuan AU - Li W AD - State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, Fujian 361005. FAU - Xia, Zongping AU - Xia Z AD - Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China. FAU - Han, Jiahuai AU - Han J AD - State Key Laboratory of Cellular Stress Biology and School of Life Sciences, Xiamen University, Xiamen, Fujian 361005. Electronic address: jhan@xmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20130423 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Amyloid) RN - 0 (Muscle Proteins) RN - EC 2.7.- (MLKL protein, human) RN - EC 2.7.- (MLKL protein, mouse) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.11.1 (RIPK3 protein, human) RN - EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Ripk3 protein, mouse) SB - IM MH - Amyloid/genetics/metabolism MH - Animals MH - Cell Line MH - Humans MH - Mice MH - Mitochondria, Muscle/metabolism/pathology MH - Muscle Cells/*enzymology/pathology MH - Muscle Proteins/genetics/*metabolism MH - Necrosis/enzymology/genetics/pathology MH - Phosphorylation/genetics MH - Protein Kinases/genetics/*metabolism MH - Receptor-Interacting Protein Serine-Threonine Kinases/genetics/*metabolism MH - *Signal Transduction PMC - PMC3675564 OTO - NOTNLM OT - Cell Death OT - MLKL OT - Necroptosis OT - Necrosis (Necrotic Death) OT - Protein Kinases OT - Protein Phosphorylation OT - Protein-Protein Interactions OT - RIP OT - RIP3 OT - Tumor Necrosis Factor (TNF) EDAT- 2013/04/25 06:00 MHDA- 2013/08/13 06:00 PMCR- 2014/06/07 CRDT- 2013/04/25 06:00 PHST- 2013/04/25 06:00 [entrez] PHST- 2013/04/25 06:00 [pubmed] PHST- 2013/08/13 06:00 [medline] PHST- 2014/06/07 00:00 [pmc-release] AID - S0021-9258(20)53637-5 [pii] AID - M112.435545 [pii] AID - 10.1074/jbc.M112.435545 [doi] PST - ppublish SO - J Biol Chem. 2013 Jun 7;288(23):16247-16261. doi: 10.1074/jbc.M112.435545. Epub 2013 Apr 23.