Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University, Richmond, VA, USA.
Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University, Richmond, VA, USA; Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
Cell Rep. 2019 Jul 9;28(2):449-459.e5. doi: 10.1016/j.celrep.2019.04.020.
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 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 discover 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 find that BGLF4 phosphorylates SAMHD1 and thereby inhibits its deoxynucleotide triphosphate triphosphohydrolase (dNTPase) activity. We further demonstrate that the targeting of SAMHD1 for phosphorylation is a common feature shared by beta- and gamma-herpesviruses. Together, our findings uncover an immune evasion mechanism whereby herpesviruses exploit the phosphorylation of SAMHD1 to thwart host defenses.
为了确保成功感染，疱疹病毒已经开发出了巧妙的策略来对抗宿主的抗病毒反应。最近，无菌α基序和 HD 结构域 1（SAMHD1）被鉴定为多种病毒的内在限制因子。除了 HIV-2 和相关的猴免疫缺陷病毒（SIV）Vpx 蛋白外，针对 SAMHD1 限制的直接病毒对策仍然未知。我们使用 EBV（Epstein-Barr virus）作为主要模型，发现 SAMHD1 介导的抗病毒限制被 EBV BGLF4 拮抗，BGLF4 是所有疱疹病毒编码的保守病毒蛋白激酶家族的成员。从机制上讲，我们发现 BGLF4 磷酸化 SAMHD1，从而抑制其脱氧核苷酸三磷酸三磷酸水解酶（dNTPase）活性。我们进一步证明，SAMHD1 磷酸化的靶向是β和γ疱疹病毒共有的一个共同特征。总之，我们的研究结果揭示了一种免疫逃避机制，疱疹病毒利用 SAMHD1 的磷酸化来破坏宿主防御。
