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

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.

Myxoma virus lacking the host range determinant M062 stimulates cGAS-dependent type 1 interferon response and unique transcriptomic changes in human macrophages

“…Other than negative feedback cascade to restrict the duration and extent of IFN-I responses, e.g., SOCS, regulation of IFN-α receptor (IFNAR), and USP18 (38-40), intracellular signaling events and miRNAs can also perform such function (41). Upstream of IFN-I production, there are also regulatory measures to pattern recognition receptors (PRRs) and their adaptors, e.g., AKT to cGAS (42), TMEM120A to STING (43), and RNF138 to TBK1 (44). Our work provides evidence of a novel mechanism to fine tune the IFN-I response, which may operate through cellular translation regulation to PRR activation ( Figure 7 ), and ultimately alters the global transcriptional landscape.…”

The curious case of TMEM120A: Mechanosensor, fat regulator, or antiviral defender?

“…Knockdown of SAR1A, SEC23A, SEC24C, SEC13 inhibited STING trafficking from the ER and its downstream signaling. [8,51,52] YIPF5 (Yip1 domain family member 5), that participates in COPII mediated-vesicle transport, was demonstrated to promote the recruitment of STING to COPII-coated vesicles. [52] These findings indicate that COPII-mediated vesicle formation is essential for STING trafficking from the ER.…”

“…For example, global knockout of Tmem120a is embryonic lethal in mice. [7,8] This indicates that Tmem120a is critical for mouse embryo development and TMEM120A might be related to genetic disorders in human. It is still unclear whether the three reported functions of Tmem120a contribute to mouse embryo development.…”

“…[ 7 ] Furthermore, in our study, we found that TMEM120A localizes to the ER membrane in HEK293T cells by the co‐immunostaining of TMEM120A with calnexin, an ER marker. [ 8 ] Although the subcellular localization of TMEM120A remains to be better defined, current reports on its localization suggest that TMEM120A might have different functions in different cell types.…”

“…[ 7 ] Recently, our group identified TMEM120A as a key regulator of the signaling of STING in antiviral response. [ 8 ] Growing evidence supports that TMEM120A has diverse functions in both physiological and pathological conditions. In this review, we will discuss the functions of TMEM120A and the underlying molecular mechanisms based on recently published work and our observations.…”