Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
PLoS Pathog. 2011 Nov;7(11):e1002336. doi: 10.1371/journal.ppat.1002336. Epub 2011 Nov 10.
Upon viral infection, mitochondrial antiviral signaling (MAVS) protein serves as a key adaptor to promote cytokine production. We report here that murine gamma herpesvirus 68 (γHV68), a model virus for oncogenic human gamma herpesviruses, subverts cytokine production via the MAVS adaptor. During early infection, γHV68 hijacks MAVS and IKKβ to induce the site-specific phosphorylation of RelA, a crucial subunit of the transcriptionally active NFκB dimer, which primes RelA for the proteasome-mediated degradation. As such, γHV68 efficiently abrogated NFκB activation and cytokine gene expression. Conversely, uncoupling RelA degradation from γHV68 infection promoted NFκB activation and elevated cytokine production. Loss of MAVS increased cytokine production and immune cell infiltration in the lungs of γHV68-infected mice. Moreover, exogenous expression of the phosphorylation- and degradation-resistant RelA variant restored γHV68-induced cytokine production. Our findings uncover an intricate strategy whereby signaling via the upstream MAVS adaptor is intercepted by a pathogen to nullify the immediate downstream effector, RelA, of the innate immune pathway.
在病毒感染时，线粒体抗病毒信号（MAVS）蛋白作为一种关键衔接蛋白，促进细胞因子的产生。我们在此报告，γ 型疱疹病毒 68（γHV68），一种致癌人类 γ 型疱疹病毒的模型病毒，通过 MAVS 衔接蛋白来破坏细胞因子的产生。在早期感染中，γHV68 劫持 MAVS 和 IKKβ，诱导转录活性 NFκB 二聚体关键亚基 RelA 的特异性磷酸化，使 RelA 为蛋白酶体介导的降解做好准备。因此，γHV68 有效地阻断了 NFκB 的激活和细胞因子基因的表达。相反，将 RelA 的降解与 γHV68 感染脱钩，促进了 NFκB 的激活和细胞因子的产生。MAVS 的缺失增加了 γHV68 感染小鼠肺部的细胞因子产生和免疫细胞浸润。此外，表达具有磷酸化和降解抗性的 RelA 变体可恢复 γHV68 诱导的细胞因子产生。我们的发现揭示了一种复杂的策略，即通过上游 MAVS 衔接蛋白的信号转导被病原体拦截，从而使先天免疫途径的直接下游效应子 RelA 失效。
