Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Protective Immunity and Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Department of Translational Medicine, Baruch S. Blumberg Research Institute, Doylestown, PA 18902, USA; Evrys Bio, Pennsylvania Biotechnology Center, Doylestown, PA 18902, USA.
Cell Rep. 2019 Jul 9;28(2):434-448.e6. doi: 10.1016/j.celrep.2019.06.027.
Cellular SAMHD1 inhibits replication of many viruses by limiting intracellular deoxynucleoside triphosphate (dNTP) pools. We investigate the influence of SAMHD1 on human cytomegalovirus (HCMV). During HCMV infection, we observe SAMHD1 induction, accompanied by phosphorylation via viral kinase UL97. SAMHD1 depletion increases HCMV replication in permissive fibroblasts and conditionally permissive myeloid cells. We show this is due to enhanced gene expression from the major immediate-early (MIE) promoter and is independent of dNTP levels. SAMHD1 suppresses innate immune responses by inhibiting nuclear factor κB (NF-κB) activation. We show that SAMHD1 regulates the HCMV MIE promoter through NF-κB activation. Chromatin immunoprecipitation reveals increased RELA and RNA polymerase II on the HCMV MIE promoter in the absence of SAMHD1. Our studies reveal a mechanism of HCMV virus restriction by SAMHD1 and show how SAMHD1 deficiency activates an innate immune pathway that paradoxically results in increased viral replication through transcriptional activation of the HCMV MIE gene promoter.
细胞 SAMHD1 通过限制细胞内脱氧核苷三磷酸 (dNTP) 池来抑制许多病毒的复制。我们研究了 SAMHD1 对人类巨细胞病毒 (HCMV) 的影响。在 HCMV 感染过程中，我们观察到 SAMHD1 的诱导，伴随着病毒激酶 UL97 的磷酸化。SAMHD1 的耗竭会增加允许的成纤维细胞和条件允许的髓样细胞中的 HCMV 复制。我们表明，这是由于主要即刻早期 (MIE) 启动子的基因表达增强，而与 dNTP 水平无关。SAMHD1 通过抑制核因子 κB (NF-κB) 激活来抑制先天免疫反应。我们表明，SAMHD1 通过 NF-κB 激活来调节 HCMV MIE 启动子。染色质免疫沉淀显示，在没有 SAMHD1 的情况下，HCMV MIE 启动子上的 RELA 和 RNA 聚合酶 II 增加。我们的研究揭示了 SAMHD1 限制 HCMV 病毒的机制，并表明 SAMHD1 缺陷如何通过先天免疫途径激活，通过 HCMV MIE 基因启动子的转录激活，导致病毒复制增加。
