Journal Article

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

Li, Mamie, Liang, Anthony, Jiang, Chao, Tan, Xu, Li, Shuo, Zu, Wenhong, Elledge, Stephen J., Qian, Nianchao

2022

Overview

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. Understanding the interplay between host and viral factors during infection is essential for the interactome of infection. Here the authors perform a gain-of-function screen to identify factors involved during Zika virus infection and identify TMEM120A as a key factor in the STING mediated immune responses.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 49/47 / 631/208/212 / 631/250/255/2514 / 631/326/596 / 631/326/596/2553 / Animals / Antiviral activity / Antiviral drugs / Apoptosis Regulatory Proteins - genetics / Apoptosis Regulatory Proteins - immunology / Cell Line, Tumor / Cell lines / Cytokines / Downstream effects / Embryo fibroblasts / Endoplasmic reticulum / Endoplasmic Reticulum - genetics / Endoplasmic Reticulum - immunology / Endoplasmic Reticulum - virology / Female / Fibroblasts / Gene Expression Regulation / Genetic screening / Genomes / Golgi apparatus / Golgi Apparatus - genetics / Golgi Apparatus - immunology / Golgi Apparatus - virology / Guillain-Barre syndrome / Hepatocytes - immunology / Hepatocytes - virology / Host-Pathogen Interactions - genetics / Host-Pathogen Interactions - immunology / Humanities and Social Sciences / Humans / Immune response / Infections / Interferon / Interferon regulatory factor 3 / Interferon Regulatory Factor-3 - genetics / Interferon Regulatory Factor-3 - immunology / Interferon-beta - genetics / Interferon-beta - immunology / Interleukin-6 - genetics / Interleukin-6 - immunology / Ion Channels - deficiency / Ion Channels - genetics / Ion Channels - immunology / Membrane Proteins - genetics / Membrane Proteins - immunology / Mice / Mice, Knockout / Microencephaly / multidisciplinary / Neonates / Phosphorylation / Protein Isoforms - genetics / Protein Isoforms - immunology / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - immunology / RNA-Binding Proteins - genetics / RNA-Binding Proteins - immunology / Science / Science (multidisciplinary) / Signal Transduction / Translocation / Vector-borne diseases / Viral Nonstructural Proteins - genetics / Viral Nonstructural Proteins - immunology / Viruses / Zika virus / Zika Virus - genetics / Zika Virus - growth & development / Zika Virus - pathogenicity / Zika Virus Infection - genetics / Zika Virus Infection - immunology / Zika Virus Infection - virology