棕榈酰化许可 TNF 通路中的 RIPK1 激酶活性和细胞毒性

IF 14.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Na Zhang, Jianping Liu, Rui Guo, Lingjie Yan, Yuanxin Yang, Chen Shi, Mengmeng Zhang, Bing Shan, Wanjin Li, Jinyang Gu, Daichao Xu
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引用次数: 0

摘要

肿瘤坏死因子(TNF)诱导的受体丝氨酸/苏氨酸蛋白激酶 1(RIPK1)介导的细胞死亡(包括细胞凋亡和坏死)越来越被认为是炎症性疾病的主要驱动因素。细胞死亡检查点通常会抑制 RIPK1 激酶,以保护生物体免受其有害后果的影响。然而,当保护性检查点失效时,许可 RIPK1 激酶活性的机制仍不清楚。在这里,我们发现S-棕榈酰化是RIPK1激酶的一种许可修饰。TNF诱导RIPK1棕榈酰化,由DHHC5介导,依赖于RIPK1的K63连接泛素化,通过促进其激酶结构域的同源相互作用增强RIPK1激酶活性,并在细胞死亡检查点阻断后促进细胞死亡。此外,在患有代谢功能障碍相关性脂肪性肝炎的小鼠肝脏中,DHHC5会被脂肪酸放大,从而导致在这种情况下观察到的RIPK1细胞毒性增强。我们的研究结果表明,泛素化依赖的棕榈酰化作用会许可 RIPK1 激酶的活性,从而诱导下游细胞死亡信号转导,这表明 RIPK1 棕榈酰化作用是治疗炎症性疾病的一个可行靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Palmitoylation licenses RIPK1 kinase activity and cytotoxicity in the TNF pathway

Palmitoylation licenses RIPK1 kinase activity and cytotoxicity in the TNF pathway
Tumor necrosis factor (TNF)-induced receptor-interacting serine/threonine protein kinase 1 (RIPK1)-mediated cell death, including apoptosis and necroptosis, is increasingly recognized as a major driver of inflammatory diseases. Cell death checkpoints normally suppress RIPK1 kinase to safeguard the organism from its detrimental consequences. However, the mechanisms licensing RIPK1 kinase activity when a protective checkpoint is disabled remain unclear. Here, we identified S-palmitoylation as a licensing modification for RIPK1 kinase. TNF induces RIPK1 palmitoylation, mediated by DHHC5 and dependent on K63-linked ubiquitination of RIPK1, which enhances RIPK1 kinase activity by promoting the homo-interaction of its kinase domain and promotes cell death upon cell death checkpoint blockade. Furthermore, DHHC5 is amplified by fatty acid in the livers of mice with metabolic dysfunction-associated steatohepatitis, contributing to increased RIPK1 cytotoxicity observed in this condition. Our findings reveal that ubiquitination-dependent palmitoylation licenses RIPK1 kinase activity to induce downstream cell death signaling and suggest RIPK1 palmitoylation as a feasible target for inflammatory diseases.
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来源期刊
Molecular Cell
Molecular Cell 生物-生化与分子生物学
CiteScore
26.00
自引率
3.80%
发文量
389
审稿时长
1 months
期刊介绍: Molecular Cell is a companion to Cell, the leading journal of biology and the highest-impact journal in the world. Launched in December 1997 and published monthly. Molecular Cell is dedicated to publishing cutting-edge research in molecular biology, focusing on fundamental cellular processes. The journal encompasses a wide range of topics, including DNA replication, recombination, and repair; Chromatin biology and genome organization; Transcription; RNA processing and decay; Non-coding RNA function; Translation; Protein folding, modification, and quality control; Signal transduction pathways; Cell cycle and checkpoints; Cell death; Autophagy; Metabolism.
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