2. Academic Validation
  3. 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

  • mBio. 2023 Apr 3;e0054923. doi: 10.1128/mbio.00549-23.
Xuezhang Tian 1 2 3 4,  Yaru Zhou 1 2,  Shaowei Wang 1 2,  Ming Gao 1 2,  Yanlin Xia 1,  Yangyang Li 2 5,  Yunhong Zhong 1 2,  Wenhao Xu 2,  Lei Bai 2 5,  Bishi Fu 2,  Yu Zhou 2 5,  Hye-Ra Lee 6 7,  Hongyu Deng 8 9,  Ke Lan 2 5,  Pinghui Feng 10,  Junjie Zhang 1 2 3 4
Affiliations

Affiliations

  • 1 State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, State Key Laboratory of Virology, Medical Research Institute, Wuhan University, Wuhan, China.
  • 2 Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China.
  • 3 Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 4 Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China.
  • 5 State Key Laboratory of Virology, School of Life Sciences, Wuhan University, Wuhan, China.
  • 6 Department of Biotechnology and Bioinformatics, College of Science and Technology, Korea University, Sejong, South Korea.
  • 7 Department of Lab Medicine, College of Medicine, Korea University, Seoul, South Korea.
  • 8 CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 9 University of Chinese Academy of Sciences, Beijing, China.
  • 10 Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA.
PMID: 37010434 DOI: 10.1128/mbio.00549-23
Abstract

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. IMPORTANCE Intrinsic immunity represents the frontline of host defense against invading pathogens. However, our understanding of cell-intrinsic Antiviral effectors remains limited. In this study, we identified SMCHD1 as a cell-intrinsic restriction factor that controlled KSHV lytic reactivation. Moreover, SMCHD1 restricted the replication of a wide range of herpesviruses by targeting the origins of viral DNA replication (ORIs), and SMCHD1 deficiency facilitated the replication of a murine herpesvirus in vivo. This study helps us to better understand intrinsic Antiviral immunity, which may be harnessed to develop new therapeutics for the treatment of herpesvirus Infection and the related diseases.

Keywords

DNA replication; KSHV; Ori-Lyt; SMCHD1; herpesvirus; restriction factor.

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