Abstract
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.
Highlights
Human cytomegalovirus (HCMV) is a ubiquitous pathogen that establishes a lifelong latent infection in the majority of the world’s population [1]
We have systematically identified viral factors that target each host protein down-regulated during the latest stage of infection, after the onset of viral DNA replication
We quantified 8,059 human and 149 viral proteins, and observed good correspondence between proteins modulated during HCMV infection in the absence of phosphonoformic acid (PFA) and protein expression in our previously published proteomic datasets [10] (SI Appendix, Fig. S1)
Summary
Human cytomegalovirus (HCMV) is a ubiquitous pathogen that establishes a lifelong latent infection in the majority of the world’s population [1]. No studies have systematically examined which host factors are targeted by viral proteins during the latest phase of infection. This question is important as some host factors may play important roles in restricting the final stages of viral replication. Previous proteomic analyses of host factors targeted for down-regulation by human cytomegalovirus (HCMV) have focused on early or intermediate stages of infection. We have systematically identified viral factors that target each host protein down-regulated during the latest stage of infection, after the onset of viral DNA replication. Our discovery that the late-expressed HCMV protein RL1 targets SLFN11 for proteasomal degradation provides evidence for a viral antagonist of this critical cellular protein. We redefine SLFN11 as an important factor that targets DNA viruses as well as RNA viruses, offering therapeutic potential via molecules that inhibit RL1-mediated SLFN11 degradation
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