Viral MLKL Homologs Subvert Necroptotic Cell Death by Sequestering Cellular RIPK3
Viral MLKL Homologs Subvert Necroptotic Cell Death by Sequestering Cellular RIPK3
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DOI：
10.1016/j.celrep.2019.08.055
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发表时间：
2019-09-24
期刊：
影响因子：
8.8
通讯作者：
Murphy, James M.
中科院分区：
文献类型：
--
作者：
Petrie, Emma J.;Sandow, Jarrod J.;Murphy, James M.
坏死性细胞死亡与许多人类病理学有关，并被认为是一种先天免疫机制。该途径依赖于两个关键效应子：激酶受体相互作用蛋白激酶3（RIPK3）和末端效应子，假激酶混合谱系激酶结构域样（MLKL）。我们鉴定了与痘病毒基因组中MLKL的假激酶结构域具有高序列相似性的蛋白质。在人和小鼠细胞中，来自BeAn 58058和Cotia痘病毒而非猪痘病毒的这些蛋白质的表达阻断了细胞MLKL活化和坏死性细胞死亡。我们表明，病毒MLKL样蛋白作为宿主MLKL的显性负性模拟物发挥作用，其通过其激酶结构域螯合RIPK3以阻止MLKL接合和磷酸化来抑制坏死性凋亡。这些数据支持坏死性凋亡在防御病原体中的祖先作用。此外，病原体对细胞假激酶的模仿增加了假激酶在信号转导中执行的功能的不断增长的库。
Necroptotic cell death has been implicated in many human pathologies and is thought to have evolved as an innate immunity mechanism. The pathway relies on two key effectors: the kinase receptor-interacting protein kinase 3 (RIPK3) and the terminal effector, the pseudokinase mixed-lineage kinase-domain-like (MLKL). We identify proteins with high sequence similarity to the pseudokinase domain of MLKL in poxvirus genomes. Expression of these proteins from the BeAn 58058 and Cotia poxviruses, but not swinepox, in human and mouse cells blocks cellular MLKL activation and necroptotic cell death. We show that viral MLKL-like proteins function as dominant-negative mimics of host MLKL, which inhibit necroptosis by sequestering RIPK3 via its kinase domain to thwart MLKL engagement and phosphorylation. These data support an ancestral role for necroptosis in defense against pathogens. Furthermore, mimicry of a cellular pseudokinase by a pathogen adds to the growing repertoire of functions performed by pseudokinases in signal transduction.