Human cytomegalovirus protein RL1 degrades the antiviral factor SLFN11 via recruitment of the CRL4 E3 ubiquitin ligase complex

Abstract

Significance Previous proteomic analyses of host factors targeted for down-regulation by human cytomegalovirus (HCMV) have focused on early or intermediate stages of infection. Using multiplexed proteomics, 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. Schlafen-11 (SLFN11), an interferon-stimulated gene and restriction factor for retroviruses and certain RNA viruses, potently restricted HCMV infection. 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 therefore 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.