Conserved Herpesvirus Protein Kinases Target SAMHD1 to Facilitate Virus Replication

To ensure a successful infection, herpesviruses have developed elegant strategies to counterbalance the host anti-viral responses. Sterile alpha motif and HD domain 1 (SAMHD1) was recently identified as an intrinsic restriction factor for a variety of viruses. Aside from human immunodeficiency virus 2 (HIV-2) and the related simian immunodeficiency virus (SIV) Vpx proteins, the direct viral countermeasures against SAMHD1 restriction remain unknown. Using Epstein-Barr virus (EBV) as a primary model, we discovered that SAMHD1-mediated anti-viral restriction is antagonized by EBV BGLF4, a member of the conserved viral protein kinases encoded by all herpesviruses. Mechanistically, we found that BGLF4 phosphorylates SAMHD1 and thereby inhibits its dNTPase activity. We further demonstrated that the targeting of SAMHD1 for phosphorylation is a common feature shared by beta- and gamma-herpesviruses. Together, our findings uncover a unique immune evasion mechanism whereby herpesviruses exploit the phosphorylation of SAMHD1 to thwart host defenses. Highlights SAMHD1 depletion facilitates EBV lytic replication. EBV protein kinase BGLF4 directly phosphorylates SAMHD1. BGLF4 phosphorylation of SAMHD1 inhibits its dCTPase and dTTPase activity. SAMHD1 is targeted by the conserved herpesvirus protein kinases. In Brief Herpesviruses have evolved elegant strategies to dampen the host anti-viral responses. Zhang et al. discover a unique mechanism by which herpesviruses evade SAMHD1-mediated host defenses through phosphorylation, expanding the functional repertoire of viral protein kinases in herpesvirus biology