p38/MK2 依赖性磷酸化控制炎症和感染中的细胞毒性 RIPK1 信号传导。

p38/MK2-dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection.

机构信息

Institute of Cell Biochemistry, Hannover Medical School, Hannover 30625, Germany.

Institute for Medical Microbiology, Virology and Hygiene, University Medical Center Eppendorf, Hamburg 20246, Germany.

出版信息

Nat Cell Biol. 2017 Oct;19(10):1248-1259. doi: 10.1038/ncb3614. Epub 2017 Sep 18.

DOI:10.1038/ncb3614

PMID:28920954

Abstract

Receptor-interacting protein kinase-1 (RIPK1), a master regulator of cell fate decisions, was identified as a direct substrate of MAPKAP kinase-2 (MK2) by phosphoproteomic screens using LPS-treated macrophages and stress-stimulated embryonic fibroblasts. p38/MK2 interact with RIPK1 in a cytoplasmic complex and MK2 phosphorylates mouse RIPK1 at Ser321/336 in response to pro-inflammatory stimuli, such as TNF and LPS, and infection with the pathogen Yersinia enterocolitica. MK2 phosphorylation inhibits RIPK1 autophosphorylation, curtails RIPK1 integration into cytoplasmic cytotoxic complexes, and suppresses RIPK1-dependent apoptosis and necroptosis. In Yersinia-infected macrophages, RIPK1 phosphorylation by MK2 protects against infection-induced apoptosis, a process targeted by Yersinia outer protein P (YopP). YopP suppresses p38/MK2 activation to increase Yersinia-driven apoptosis. Hence, MK2 phosphorylation of RIPK1 is a crucial checkpoint for cell fate in inflammation and infection that determines the outcome of bacteria-host cell interaction.

摘要

受体相互作用蛋白激酶-1（RIPK1）是细胞命运决定的主要调节因子，通过使用脂多糖处理的巨噬细胞和应激刺激的胚胎成纤维细胞进行磷酸蛋白质组筛选，被鉴定为丝裂原活化蛋白激酶激酶-2（MK2）的直接底物。p38/MK2 在细胞质复合物中与 RIPK1 相互作用，MK2 响应促炎刺激（如 TNF 和 LPS）以及感染病原体肠侵袭性大肠杆菌，在 Ser321/336 处磷酸化鼠 RIPK1。MK2 磷酸化抑制 RIPK1 自身磷酸化，限制 RIPK1 整合到细胞质细胞毒性复合物中，并抑制 RIPK1 依赖性细胞凋亡和坏死性凋亡。在感染肠侵袭性大肠杆菌的巨噬细胞中，MK2 对 RIPK1 的磷酸化可防止感染诱导的细胞凋亡，该过程是由肠侵袭性大肠杆菌外蛋白 P（YopP）靶向的。YopP 抑制 p38/MK2 的激活，以增加肠侵袭性大肠杆菌驱动的细胞凋亡。因此，RIPK1 的 MK2 磷酸化是炎症和感染中细胞命运的关键检查点，决定了细菌与宿主细胞相互作用的结果。