Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Cell Host Microbe. 2010 Apr 22;7(4):302-313. doi: 10.1016/j.chom.2010.03.006.
Viral infection activates cytokine expression and triggers cell death, the modulation of which is important for successful pathogenesis. Necroptosis is a form of programmed necrosis dependent on two related RIP homotypic interaction motif (RHIM)-containing signaling adaptors, receptor-interacting protein kinases (RIP) 1 and 3. We find that murine cytomegalovirus infection induces RIP3-dependent necrosis. Whereas RIP3 kinase activity and RHIM-dependent interactions control virus-associated necrosis, virus-induced death proceeds independently of RIP1 and is therefore distinct from TNFalpha-dependent necroptosis. Viral M45-encoded inhibitor of RIP activation (vIRA) targets RIP3 during infection and disrupts RIP3-RIP1 interactions characteristic of TNFalpha-induced necroptosis, thereby suppressing both death pathways. Importantly, attenuation of vIRA mutant virus in wild-type mice is normalized in RIP3-deficient mice. Thus, vIRA function validates necrosis as central to host defense against viral infections and highlights the benefit of multiple virus-encoded cell-death suppressors that inhibit not only apoptotic, but also necrotic mechanisms of virus clearance.
病毒感染会激活细胞因子的表达并引发细胞死亡，而对其进行调控对于成功的发病机制非常重要。细胞程序性坏死依赖于两种相关的 RIP 同型相互作用基序（RHIM）结合信号衔接蛋白，即受体相互作用蛋白激酶（RIP）1 和 3。我们发现，鼠巨细胞病毒感染会诱导 RIP3 依赖性坏死。虽然 RIP3 激酶活性和 RHIM 依赖性相互作用控制与病毒相关的坏死，但病毒诱导的死亡过程不依赖于 RIP1，因此与 TNFalpha 依赖性细胞程序性坏死不同。病毒编码的 RIP 激活抑制剂（vIRA）在感染期间靶向 RIP3，并破坏 TNFalpha 诱导的细胞程序性坏死中特征性的 RIP3-RIP1 相互作用，从而抑制这两种死亡途径。重要的是，野生型小鼠中 vIRA 突变病毒的衰减在 RIP3 缺陷型小鼠中得到了正常化。因此，vIRA 功能证实了坏死在宿主防御病毒感染中的核心作用，并强调了多种病毒编码的细胞死亡抑制剂的益处，这些抑制剂不仅抑制凋亡，还抑制病毒清除的坏死机制。
