Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom.
Department of Medicine, University of Cambridge, Cambridge CB2 0XY, United Kingdom.
Proc Natl Acad Sci U S A. 2022 Feb 8;119(6). doi: 10.1073/pnas.2108173119.
Human cytomegalovirus (HCMV) is an important human pathogen and a paradigm of viral immune evasion, targeting intrinsic, innate, and adaptive immunity. We have employed two orthogonal multiplexed tandem mass tag-based proteomic screens to identify host proteins down-regulated by viral factors expressed during the latest phases of viral infection. This approach revealed that the HIV-1 restriction factor Schlafen-11 (SLFN11) was degraded by the poorly characterized, late-expressed HCMV protein RL1, via recruitment of the Cullin4-RING E3 Ubiquitin Ligase (CRL4) complex. SLFN11 potently restricted HCMV infection, inhibiting the formation and spread of viral plaques. Overall, we show that a restriction factor previously thought only to inhibit RNA viruses additionally restricts HCMV. We define the mechanism of viral antagonism and also describe an important resource for revealing additional molecules of importance in antiviral innate immunity and viral immune evasion.
人类巨细胞病毒（HCMV）是一种重要的人类病原体，也是病毒免疫逃避的典范，针对固有免疫、先天免疫和适应性免疫。我们采用了两种正交的多重串联质量标签基于蛋白质组学筛选方法，以鉴定在病毒感染的最新阶段表达的病毒因子下调的宿主蛋白。这种方法揭示了 HIV-1 限制因子 Schlafen-11（SLFN11）通过招募 Cullin4-RING E3 泛素连接酶（CRL4）复合物，被特征不明确的晚期表达的 HCMV 蛋白 RL1 降解。SLFN11 强烈限制了 HCMV 的感染，抑制了病毒斑的形成和扩散。总的来说，我们表明，以前被认为仅抑制 RNA 病毒的一种限制因子，还额外限制了 HCMV。我们定义了病毒拮抗的机制，也描述了一个重要的资源，用于揭示抗病毒先天免疫和病毒免疫逃避中其他重要分子。
