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^MAPK/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^MAPK/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.

中文翻译：

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p38MAPK / 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

受体相互作用蛋白激酶1（RIPK1），细胞命运决定的主要调节器，通过LPS处理的巨噬细胞和应激刺激的胚胎成纤维细胞的磷酸化蛋白质组学筛选，被鉴定为MAPKAP激酶2（MK2）的直接底物。p38 ^MAPK / MK2与细胞质复合物中的RIPK1相互作用，MK2在Ser321 / 336处使小鼠RIPK1磷酸化，以响应促炎性刺激（例如TNF和LPS）以及病原体小肠结肠炎耶尔森氏菌感染。MK2磷酸化抑制RIPK1自磷酸化，减少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坏死。在耶尔森尼亚感染巨噬细胞后，MIP2使RIPK1磷酸化，从而防止感染诱导的细胞凋亡，这是耶尔森氏菌外蛋白P（YopP）靶向的过程。YopP抑制p38 ^MAPK / MK2活化，以增加耶尔森氏菌驱动的细胞凋亡。因此，RIPK1的MK2磷酸化是决定细菌与宿主细胞相互作用结果的炎症和感染中细胞命运的关键检查点。