Genome-Wide CRISPR-Cas9 Screen Identifies SMCHD1 as a Restriction Factor for Herpesviruses.
Genome-Wide CRISPR-Cas9 Screen Identifies SMCHD1 as a Restriction Factor for Herpesviruses.
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固有免疫是宿主防御入侵病原体的前线。为了对抗病毒感染，哺乳动物宿主在先天性和适应性免疫开始之前部署细胞内在效应物以阻断病毒复制。在这项研究中，SMCHD 1被确定为一种关键的细胞因子，通过全基因组CRISPR-Cas9敲除筛选限制卡波西肉瘤相关疱疹病毒（KSHV）裂解再激活。全基因组染色质分析显示，SMCHD 1与KSHV基因组相关，最突出的是裂解DNA复制起点（ORI-Lyt）。DNA结合缺陷的SMCHD 1突变体不能结合ORI-Lyt，也不能限制KSHV裂解性复制。此外，SMCHD 1作为泛疱疹病毒限制因子发挥作用，有效抑制广泛的疱疹病毒，包括α，β和γ亚科。SMCHD 1缺陷促进了鼠疱疹病毒在体内的复制。这些发现揭示了SMCHD 1作为针对疱疹病毒的限制因子，这可以用于开发抗病毒疗法以限制病毒感染。
Intrinsic immunity is the frontline of host defense against invading pathogens. To combat viral infection, mammalian hosts deploy cell-intrinsic effectors to block viral replication prior to the onset of innate and adaptive immunity. In this study, SMCHD1 is identified as a pivotal cellular factor that restricts Kaposi’s sarcoma-associated herpesvirus (KSHV) lytic reactivation through a genome-wide CRISPR-Cas9 knockout screen. Genome-wide chromatin profiling revealed that SMCHD1 associates with the KSHV genome, most prominently the origin of lytic DNA replication (ORI-Lyt). SMCHD1 mutants defective in DNA binding could not bind ORI-Lyt and failed to restrict KSHV lytic replication. Moreover, SMCHD1 functioned as a pan-herpesvirus restriction factor that potently suppressed a wide range of herpesviruses, including alpha, beta, and gamma subfamilies. SMCHD1 deficiency facilitated the replication of a murine herpesvirus in vivo. These findings uncovered SMCHD1 as a restriction factor against herpesviruses, and this could be harnessed for the development of antiviral therapies to limit viral infection.
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