Genome-Wide CRISPR-Cas9 Screen Identifies SMCHD1 as a Restriction Factor for Herpesviruses
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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2023-04-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00549-23 |
| _version_ | 1797839611492302848 |
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| author | Xuezhang Tian Yaru Zhou Shaowei Wang Ming Gao Yanlin Xia Yangyang Li Yunhong Zhong Wenhao Xu Lei Bai Bishi Fu Yu Zhou Hye-Ra Lee Hongyu Deng Ke Lan Pinghui Feng Junjie Zhang |
| author_facet | Xuezhang Tian Yaru Zhou Shaowei Wang Ming Gao Yanlin Xia Yangyang Li Yunhong Zhong Wenhao Xu Lei Bai Bishi Fu Yu Zhou Hye-Ra Lee Hongyu Deng Ke Lan Pinghui Feng Junjie Zhang |
| author_sort | Xuezhang Tian |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T15:59:37Z |
| format | Article |
| id | doaj.art-7bba3875177843adaaca05f630676f93 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-04-09T15:59:37Z |
| publishDate | 2023-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-7bba3875177843adaaca05f630676f932023-04-25T13:04:57ZengAmerican Society for MicrobiologymBio2150-75112023-04-0114210.1128/mbio.00549-23Genome-Wide CRISPR-Cas9 Screen Identifies SMCHD1 as a Restriction Factor for HerpesvirusesXuezhang Tian0Yaru Zhou1Shaowei Wang2Ming Gao3Yanlin Xia4Yangyang Li5Yunhong Zhong6Wenhao Xu7Lei Bai8Bishi Fu9Yu Zhou10Hye-Ra Lee11Hongyu Deng12Ke Lan13Pinghui Feng14Junjie Zhang15State 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, ChinaState 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, ChinaState 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, ChinaState 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, ChinaState 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, ChinaFrontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, ChinaState 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, ChinaFrontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, ChinaFrontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, ChinaFrontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, ChinaFrontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, ChinaDepartment of Biotechnology and Bioinformatics, College of Science and Technology, Korea University, Sejong, South KoreaCAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, ChinaFrontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, ChinaSection of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USAState 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, ChinaABSTRACT 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.https://journals.asm.org/doi/10.1128/mbio.00549-23DNA replicationKSHVOri-LytSMCHD1herpesvirusrestriction factor |
| spellingShingle | Xuezhang Tian Yaru Zhou Shaowei Wang Ming Gao Yanlin Xia Yangyang Li Yunhong Zhong Wenhao Xu Lei Bai Bishi Fu Yu Zhou Hye-Ra Lee Hongyu Deng Ke Lan Pinghui Feng Junjie Zhang Genome-Wide CRISPR-Cas9 Screen Identifies SMCHD1 as a Restriction Factor for Herpesviruses mBio DNA replication KSHV Ori-Lyt SMCHD1 herpesvirus restriction factor |
| title | Genome-Wide CRISPR-Cas9 Screen Identifies SMCHD1 as a Restriction Factor for Herpesviruses |
| title_full | Genome-Wide CRISPR-Cas9 Screen Identifies SMCHD1 as a Restriction Factor for Herpesviruses |
| title_fullStr | Genome-Wide CRISPR-Cas9 Screen Identifies SMCHD1 as a Restriction Factor for Herpesviruses |
| title_full_unstemmed | Genome-Wide CRISPR-Cas9 Screen Identifies SMCHD1 as a Restriction Factor for Herpesviruses |
| title_short | Genome-Wide CRISPR-Cas9 Screen Identifies SMCHD1 as a Restriction Factor for Herpesviruses |
| title_sort | genome wide crispr cas9 screen identifies smchd1 as a restriction factor for herpesviruses |
| topic | DNA replication KSHV Ori-Lyt SMCHD1 herpesvirus restriction factor |
| url | https://journals.asm.org/doi/10.1128/mbio.00549-23 |
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