PMID- 37010434
OWN - NLM
STAT- MEDLINE
DCOM- 20230427
LR  - 20231019
IS  - 2150-7511 (Electronic)
VI  - 14
IP  - 2
DP  - 2023 Apr 25
TI  - Genome-Wide CRISPR-Cas9 Screen Identifies SMCHD1 as a Restriction Factor for 
      Herpesviruses.
PG  - e0054923
LID - 10.1128/mbio.00549-23 [doi]
LID - e00549-23
AB  - 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.
FAU - Tian, Xuezhang
AU  - Tian X
AD  - 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.
AD  - Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 
      China.
AD  - Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan 
      University, Wuhan, China.
AD  - Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of 
      Medical Sciences, Wuhan, China.
FAU - Zhou, Yaru
AU  - Zhou Y
AD  - 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.
AD  - Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 
      China.
FAU - Wang, Shaowei
AU  - Wang S
AD  - 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.
AD  - Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 
      China.
FAU - Gao, Ming
AU  - Gao M
AD  - 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.
AD  - Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 
      China.
FAU - Xia, Yanlin
AU  - Xia Y
AD  - 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.
FAU - Li, Yangyang
AU  - Li Y
AD  - Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 
      China.
AD  - State Key Laboratory of Virology, School of Life Sciences, Wuhan University, 
      Wuhan, China.
FAU - Zhong, Yunhong
AU  - Zhong Y
AD  - 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.
AD  - Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 
      China.
FAU - Xu, Wenhao
AU  - Xu W
AD  - Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 
      China.
FAU - Bai, Lei
AU  - Bai L
AD  - Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 
      China.
AD  - State Key Laboratory of Virology, School of Life Sciences, Wuhan University, 
      Wuhan, China.
FAU - Fu, Bishi
AU  - Fu B
AD  - Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 
      China.
FAU - Zhou, Yu
AU  - Zhou Y
AUID- ORCID: 0000-0002-2102-9377
AD  - Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 
      China.
AD  - State Key Laboratory of Virology, School of Life Sciences, Wuhan University, 
      Wuhan, China.
FAU - Lee, Hye-Ra
AU  - Lee HR
AD  - Department of Biotechnology and Bioinformatics, College of Science and 
      Technology, Korea University, Sejong, South Korea.
AD  - Department of Lab Medicine, College of Medicine, Korea University, Seoul, South 
      Korea.
FAU - Deng, Hongyu
AU  - Deng H
AUID- ORCID: 0000-0001-6703-6313
AD  - CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in 
      Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 
      China.
AD  - University of Chinese Academy of Sciences, Beijing, China.
FAU - Lan, Ke
AU  - Lan K
AUID- ORCID: 0000-0002-0384-8598
AD  - Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 
      China.
AD  - State Key Laboratory of Virology, School of Life Sciences, Wuhan University, 
      Wuhan, China.
FAU - Feng, Pinghui
AU  - Feng P
AUID- ORCID: 0000-0002-8494-0205
AD  - Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris 
      Comprehensive Cancer Center, University of Southern California, Los Angeles, 
      California, USA.
FAU - Zhang, Junjie
AU  - Zhang J
AUID- ORCID: 0000-0003-3812-3850
AD  - 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.
AD  - Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 
      China.
AD  - Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan 
      University, Wuhan, China.
AD  - Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of 
      Medical Sciences, Wuhan, China.
LA  - eng
GR  - R01 CA221521/CA/NCI NIH HHS/United States
GR  - R21 AI134105/AI/NIAID NIH HHS/United States
GR  - R35 DE027556/DE/NIDCR NIH HHS/United States
GR  - R01 DE026003/DE/NIDCR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230403
PL  - United States
TA  - mBio
JT  - mBio
JID - 101519231
RN  - 0 (DNA, Viral)
RN  - 0 (SmcHD1 protein, mouse)
RN  - 0 (Chromosomal Proteins, Non-Histone)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Virus Replication/genetics
MH  - DNA Replication
MH  - CRISPR-Cas Systems
MH  - DNA, Viral/genetics
MH  - *Herpesvirus 8, Human/physiology
MH  - Gene Expression Regulation, Viral
MH  - Mammals/metabolism
MH  - Chromosomal Proteins, Non-Histone/genetics
PMC - PMC10128004
OTO - NOTNLM
OT  - DNA replication
OT  - KSHV
OT  - Ori-Lyt
OT  - SMCHD1
OT  - herpesvirus
OT  - restriction factor
COIS- The authors declare no conflict of interest.
EDAT- 2023/04/04 06:00
MHDA- 2023/04/27 06:42
PMCR- 2023/04/03
CRDT- 2023/04/03 10:15
PHST- 2023/04/27 06:42 [medline]
PHST- 2023/04/04 06:00 [pubmed]
PHST- 2023/04/03 10:15 [entrez]
PHST- 2023/04/03 00:00 [pmc-release]
AID - 00549-23 [pii]
AID - mbio.00549-23 [pii]
AID - 10.1128/mbio.00549-23 [doi]
PST - ppublish
SO  - mBio. 2023 Apr 25;14(2):e0054923. doi: 10.1128/mbio.00549-23. Epub 2023 Apr 3.