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.

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Mechanical pain sensing, adipogenesis, and STING‐dependent innate immunity seem three distinct biological processes without substantial relationships. Intriguingly, TMEM120A, a transmembrane protein, has been shown to detect mechanical pain stimuli as a mechanosensitive channel, contribute to adipocyte differentiation/function by regulating genome organization and promote STING trafficking to active cellular innate immune response. However, the role of TMEM120A as a mechanosensitive channel was challenged by recent studies which cannot reproduce data supporting its role in mechanosensing. Furthermore, the molecular mechanism by which TMEM120A contributes to adipocyte differentiation/function and promotes STING trafficking remains elusive. In this review, we discuss these multiple proposed functions of TMEM120A and hypothesize the molecular mechanism underlying TMEM120A's role in fatty acid metabolism and STING signaling.