Manipulation of apoptosis and necroptosis signaling by herpesviruses.
Manipulation of apoptosis and necroptosis signaling by herpesviruses.
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DOI：
10.1007/s00430-015-0410-5
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发表时间：
2015-06
影响因子：
5.4
通讯作者：
Mocarski ES
中科院分区：
文献类型：
--
作者：
Guo H;Kaiser WJ;Mocarski ES
与细胞凋亡一样，坏死性凋亡是一种消除病原体感染细胞的先天免疫机制。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的病毒而触发的。在小鼠CMV中，半胱天冬酶8激活的病毒抑制剂（vICA）可防止外源性凋亡，但也有可能释放坏死性凋亡。该病毒编码RIP激活的病毒抑制剂（vIRA），以防止RIP同型相互作用基序（RHIM）依赖的信号转导和坏死性凋亡。最近的研究揭示了在人类α疱疹病毒、单纯疱疹病毒（HSV）1和HSV 2中起作用的类似机制，其中RHIM竞争剂功能和半胱天冬酶8抑制由病毒编码的核糖核苷酸还原酶大亚基（R1）进行。在人类细胞中，R1抑制caspase 8可防止TNF诱导的细胞凋亡，但对TNF诱导的坏死性凋亡敏感。R1的RHIM和半胱天冬酶8相互作用结构域合作，以防止RIP3依赖的步骤，并使两种疱疹病毒能够偏转宿主细胞死亡机制，从而缩短感染。在小鼠细胞中，HSV 1感染本身通过驱动RIP3蛋白激酶活性引发坏死性凋亡。HSV1R1有助于小鼠中RIP3衔接子功能的激活，小鼠是实验感染的流行宿主动物。基于这些研究，RIP3激酶失活小鼠的感染应在发病机制和潜伏期模型中进行探索。在自然宿主中感染期间被抑制的坏死性死亡途径成为非自然宿主中感染的跨种属屏障。
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 (vICA) prevents extrinsic apoptosis but also has the potential to unleash necroptosis. This virus encodes the viral inhibitor of RIP activation (vIRA) to prevent RIP homotypic interaction motif (RHIM)-dependent signal transduction and necroptosis. Recent investigations reveal a similar mechanism at play in the human alphaherpesviruses, 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 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.