TNF is a master proinflammatory cytokine whose pathogenic role in inflammatory disorders can, in certain conditions, be attributed to RIPK1 kinase-dependent cell death. Survival, however, is the default response of most cells to TNF stimulation, indicating that cell demise is normally actively repressed and that specific checkpoints must be turned off for cell death to proceed. We identified RIPK1 as a direct substrate of MK2 in the TNFR1 signalling pathway. Phosphorylation of RIPK1 by MK2 limits cytosolic activation of RIPK1 and the subsequent assembly of the death complex that drives RIPK1 kinase-dependent apoptosis and necroptosis. In line with these in vitro findings, MK2 inactivation greatly sensitizes mice to the cytotoxic effects of TNF in an acute model of sterile shock caused by RIPK1-dependent cell death. In conclusion, we identified MK2-mediated RIPK1 phosphorylation as an important molecular mechanism limiting the sensitivity of the cells to the cytotoxic effects of TNF.

中文翻译：

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RIPK1的MK2磷酸化调节TNF介导的细胞死亡

TNF是主要的促炎细胞因子，其在炎症性疾病中的致病作用在某些情况下可归因于RIPK1激酶依赖性细胞死亡。但是，存活率是大多数细胞对TNF刺激的默认反应，这表明通常可以积极抑制细胞死亡，并且必须关闭特定的检查点才能继续进行细胞死亡。我们确定RIPK1为TNFR1信号通路中MK2的直接底物。MIP2对RIPK1的磷酸化作用限制了RIPK1的胞质活化以及随后驱动RIPK1激酶依赖性细胞凋亡和坏死性死亡的死亡复合体的组装。符合这些体外研究发现，在由RIPK1依赖性细胞死亡引起的无菌休克急性模型中，MK2失活极大地使小鼠对TNF的细胞毒性作用敏感。总之，我们确定MK2介导的RIPK1磷酸化是限制细胞对TNF的细胞毒性作用的敏感性的重要分子机制。