Gain-of-function genetic screening identifies the antiviral function of TMEM120A via STING activation

Shuo Li, Nianchao Qian, Chao Jiang, Wenhong Zu, Anthony Liang, Mamie Li, Stephen J. Elledge and Xu Tan ()
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Shuo Li: Tsinghua University
Nianchao Qian: Tsinghua University
Chao Jiang: Tsinghua University
Wenhong Zu: Tsinghua University
Anthony Liang: Division of Genetics, Brigham and Women’s Hospital, Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School
Mamie Li: Division of Genetics, Brigham and Women’s Hospital, Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School
Stephen J. Elledge: Division of Genetics, Brigham and Women’s Hospital, Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School
Xu Tan: Tsinghua University

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract Zika virus (ZIKV) infection can be associated with neurological pathologies, such as microcephaly in newborns and Guillain-Barre syndrome in adults. Effective therapeutics are currently not available. As such, a comprehensive understanding of virus-host interactions may guide the development of medications for ZIKV. Here we report a human genome-wide overexpression screen to identify host factors that regulate ZIKV infection and find TMEM120A as a ZIKV restriction factor. TMEM120A overexpression significantly inhibits ZIKV replication, while TMEM120A knockdown increases ZIKV infection in cell lines. Moreover, Tmem120a knockout in mice facilitates ZIKV infection in primary mouse embryonic fibroblasts (MEF) cells. Mechanistically, the antiviral activity of TMEM120A is dependent on STING, as TMEM120A interacts with STING, promotes the translocation of STING from the endoplasmic reticulum (ER) to ER-Golgi intermediate compartment (ERGIC) and enhances the phosphorylation of downstream TBK1 and IRF3, resulting in the expression of multiple antiviral cytokines and interferon-stimulated genes. In summary, our gain-of-function screening identifies TMEM120A as a key activator of the antiviral signaling of STING.

Date: 2022
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DOI: 10.1038/s41467-021-27670-1

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