2. Academic Validation
  3. Dual inhibition of innate immunity and apoptosis by human cytomegalovirus protein UL37x1 enables efficient virus replication

Dual inhibition of innate immunity and apoptosis by human cytomegalovirus protein UL37x1 enables efficient virus replication

  • Nat Microbiol. 2022 Jul;7(7):1041-1053. doi: 10.1038/s41564-022-01136-6.
Yujie Ren 1 2,  An Wang 2 3,  Di Wu 2,  Chong Wang 1 2,  Muhan Huang 2,  Xiaobei Xiong 2,  Liang Jin 4,  Wei Zhou 5,  Yang Qiu 6 7,  Xi Zhou 8 9 10
Affiliations

Affiliations

  • 1 Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong, China.
  • 2 State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China.
  • 3 University of Chinese Academy of Sciences, Beijing, China.
  • 4 Institute of Microbiology, Jiangxi Academy of Sciences, Nanchang, Jiangxi, China.
  • 5 Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong, China. zhouwei_pu002@126.com.
  • 6 State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China. yangqiu@wh.iov.cn.
  • 7 University of Chinese Academy of Sciences, Beijing, China. yangqiu@wh.iov.cn.
  • 8 State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China. zhouxi@wh.iov.cn.
  • 9 University of Chinese Academy of Sciences, Beijing, China. zhouxi@wh.iov.cn.
  • 10 Institute of Microbiology, Jiangxi Academy of Sciences, Nanchang, Jiangxi, China. zhouxi@wh.iov.cn.
PMID: 35637330 DOI: 10.1038/s41564-022-01136-6
Abstract

Immune evasion and inhibition of Apoptosis are required for successful virus Infection. However, inhibition of Apoptosis can increase Antiviral immune responses, which can then clear viral infections. Here we show that human cytomegalovirus (HCMV)-encoded UL37 exon-1 protein (UL37x1) not only inhibits Apoptosis but also suppresses the cGAS-STING immune pathway. Using co-immunoprecipitation assays, we found that UL37x1 binds to TBK1 to abrogate the TBK1-STING-IRF3 interaction. Although the anti-apoptosis function of UL37x1 increases immune signalling, the immunosuppressive role of UL37x1 counteracts this undesirable side-effect. Furthermore, we used mutational analyses to show that the loss of either immunosuppressive or anti-apoptotic function of UL37x1 significantly reduced HCMV replication in human primary foreskin fibroblasts and humanized mice by over twofold. Finally, loss of both functions resulted in over fourfold reduction of HCMV replication in the same cell type and mouse model, showing that both UL37x1 functions are crucial for HCMV Infection. We conclude that this sophisticated mechanism enables HCMV to control innate immunity and Apoptosis to ensure efficient Infection.

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