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Abstract
SummaryHuman cytomegalovirus (HCMV) is an important pathogen with multiple immune evasion strategies, including virally facilitated degradation of host antiviral restriction factors. Here, we describe a multiplexed approach to discover proteins with innate immune function on the basis of active degradation by the proteasome or lysosome during early-phase HCMV infection. Using three orthogonal proteomic/transcriptomic screens to quantify protein degradation, with high confidence we identified 35 proteins enriched in antiviral restriction factors. A final screen employed a comprehensive panel of viral mutants to predict viral genes that target >250 human proteins. This approach revealed that helicase-like transcription factor (HLTF), a DNA helicase important in DNA repair, potently inhibits early viral gene expression but is rapidly degraded during infection. The functionally unknown HCMV protein UL145 facilitates HLTF degradation by recruiting the Cullin4 E3 ligase complex. Our approach and data will enable further identifications of innate pathways targeted by HCMV and other viruses.
Highlights
Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that persistently infects the majority of the world’s population (Mocarski et al, 2013)
Host Proteins Targeted for Degradation Early during HCMV Infection To build a detailed global picture of all host proteins that are degraded during early HCMV infection, we applied the proteasomal inhibitor MG132 or the lysosomal protease inhibitor leupeptin at three early time points during infection of immortalized primary human fetal foreskin fibroblasts (HFFF-TERTs)
Virus inactivated by irradiation (HCMV*) was included in the experiment to determine whether components of the virion delivered during the process of infection made a contribution
Summary
Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that persistently infects the majority of the world’s population (Mocarski et al, 2013). Reactivation from viral latency to productive infection causes serious disease in immunocompromised individuals, transplant recipients and AIDS patients (Nichols et al, 2002). Primary infection and reactivation in utero are leading causes of deafness and mental retardation in newborns, affecting approximately 1 in 200 pregnancies (Mocarski et al, 2013). Susceptibility to viral infection and disease is determined in part by antiviral restriction factors (ARFs) and the viral proteins that have evolved to degrade them (Duggal and Emerman, 2012). The identification and characterization of ARFs has important implications for antiviral therapy, and is important for HCMV, for which only a few drugs are available
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