Guo Hongyan, Kaiser William J, Mocarski Edward S
Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Med Microbiol Immunol. 2015 Jun;204(3):439-48. doi: 10.1007/s00430-015-0410-5. Epub 2015 Apr 1.
Like apoptosis, necroptosis is an innate immune mechanism that eliminates pathogen-infected cells. Receptor-interacting protein kinase (RIP)3 (also called RIPK3) mediates necrotic death by phosphorylating an executioner protein, MLKL, leading to plasma membrane leakage. The pathway is triggered against viruses that block caspase 8. In murine CMV, the viral inhibitor of caspase 8 activation prevents extrinsic apoptosis but also has the potential to unleash necroptosis. This virus encodes the viral inhibitor of RIP activation to prevent RIP homotypic interaction motif (RHIM)-dependent signal transduction and necroptosis. Recent investigations reveal a similar mechanism at play in the human alpha-herpesviruses, herpes simplex virus (HSV)1 and HSV2, where RHIM competitor function and caspase 8 suppression are carried out by the virus-encoded large subunit of ribonucleotide reductase (R1). In human cells, R1 inhibition of caspase 8 prevents TNF-induced apoptosis, but sensitizes to TNF-induced necroptosis. The RHIM and caspase 8 interaction domains of R1 collaborate to prevent RIP3-dependent steps and enable both herpesviruses to deflect host cell death machinery that would cut short infection. In mouse cells, HSV1 infection by itself triggers necroptosis by driving RIP3 protein kinase activity. HSV1 R1 contributes to the activation of RIP3 adaptor function in mice, a popular host animal for experimental infection. Based on these studies, infection of RIP3-kinase inactive mice should be explored in models of pathogenesis and latency. The necrotic death pathway that is suppressed during infection in the natural host becomes a cross-species barrier to infection in a non-natural host.
与凋亡一样，坏死性凋亡是一种消除病原体感染细胞的固有免疫机制。受体相互作用蛋白激酶（RIP）3（也称为RIPK3）通过磷酸化执行蛋白MLKL介导坏死性死亡，导致质膜渗漏。该途径是针对阻断半胱天冬酶8的病毒触发的。在鼠巨细胞病毒中，半胱天冬酶8激活的病毒抑制剂可防止外源性凋亡，但也有可能引发坏死性凋亡。这种病毒编码RIP激活的病毒抑制剂，以防止RIP同型相互作用基序（RHIM）依赖性信号转导和坏死性凋亡。最近的研究揭示了人类α-疱疹病毒单纯疱疹病毒（HSV）1和HSV2中类似的机制，其中RHIM竞争功能和半胱天冬酶8抑制由病毒编码的核糖核苷酸还原酶大亚基（R1）执行。在人类细胞中，R1对半胱天冬酶8的抑制可防止肿瘤坏死因子（TNF）诱导的凋亡，但会使细胞对TNF诱导的坏死性凋亡敏感。R1的RHIM和半胱天冬酶8相互作用域协同作用，以防止RIP3依赖性步骤，并使两种疱疹病毒都能避开会缩短感染时间的宿主细胞死亡机制。在小鼠细胞中，HSV1感染本身通过驱动RIP3蛋白激酶活性触发坏死性凋亡。HSV1 R1有助于激活小鼠中RIP3衔接蛋白的功能，小鼠是实验性感染常用的宿主动物。基于这些研究，应在发病机制和潜伏期模型中探索RIP3激酶失活小鼠的感染情况。在天然宿主感染期间被抑制的坏死性死亡途径成为非天然宿主感染的跨物种障碍。
