Residue Y362 is crucial for FLIP L to impart catalytic activity to pro-caspase-8 to suppress necroptosis.

Autor: Hong M; State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China., Wu X; Zhejiang Provincial Key Laboratory of Pancreatic Disease, MOE Joint International Research Laboratory of Pancreatic Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310012, China., He P; State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China., Peng R; State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China., Li L; State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China., Wu SQ; Laboratory Animal Center, Xiamen University, Xiamen, Fujian 361102, China., Zhao J; State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China., Han A; State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China., Zhang Y; State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. Electronic address: y.zhang@xmu.edu.cn., Han J; State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; Laboratory Animal Center, Xiamen University, Xiamen, Fujian 361102, China. Electronic address: jhan@xmu.edu.cn., Yang ZH; Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310012, China. Electronic address: zhanghuayang@zju.edu.cn.
Jazyk: angličtina
Zdroj: Cell reports [Cell Rep] 2024 Nov 26; Vol. 43 (11), pp. 114966. Date of Electronic Publication: 2024 Nov 08.
DOI: 10.1016/j.celrep.2024.114966
Abstrakt: The pro-form of caspase-8 prevents necroptosis by functioning in a proteolytically active complex with its catalytic-dead homolog, FLICE (FADD [Fas-associated death domain]-like interleukin 1β-converting enzyme)-like inhibitory protein long-form (FLIP L ). However, how FLIP L imparts caspase-8 the catalytic activity to suppress necroptosis remains elusive. Here, we show that the protease-like domain of FLIP L is essential for the activity of the caspase-8-FLIP L heterodimer in blocking necroptosis. While substitution of two amino acids whose difference may contribute to the pseudo-caspase property of FLIP L with the corresponding amino acids in caspase-8 does not restore the protease activity of FLIP L , one of the amino acid replacements, tyrosine (Y) 362 to cysteine (C), is sufficient to completely abolish the activity of the caspase-8-FLIP L heterodimer in cleaving receptor-interacting protein 1 (RIP1), thus releasing the necroptosis blockade. Unconstrained necroptosis is observed in embryonic day (E)10.5-E11.5 embryos of FLIP L -Y362C knockin mice. Collectively, these results reveal that the protease-like domain of FLIP L has a special structure that imparts the pro-caspase-8-FLIP L heterodimer a unique catalytic activity toward RIP1 to prevent necroptosis.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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