The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
Cell Rep. 2019 Sep 24;28(13):3309-3319.e5. doi: 10.1016/j.celrep.2019.08.055.
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.
细胞坏死性细胞死亡与许多人类病理学有关，并被认为是作为先天免疫机制而进化的。该途径依赖于两个关键效应物：激酶受体相互作用蛋白激酶 3（RIPK3）和末端效应物，假激酶混合谱系激酶结构域样（MLKL）。我们在痘病毒基因组中鉴定出与 MLKL 的假激酶结构域具有高度序列相似性的蛋白质。来自 BeAn 58058 和 Cotia 痘病毒的这些蛋白质的表达，但不是猪痘病毒，在人源和鼠源细胞中阻断细胞 MLKL 激活和坏死性细胞死亡。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，通过其激酶结构域将 RIPK3 隔离来阻止 MLKL 结合和磷酸化，从而抑制坏死性细胞死亡。这些数据支持坏死性细胞死亡在防御病原体方面的古老作用。此外，病原体对细胞假激酶的模拟增加了信号转导中假激酶执行的功能的不断增长的功能。
