Date Published: February 22, 2016
Publisher: Public Library of Science
Author(s): Wei Chen, Senlin Li, Huansha Yu, Xing Liu, Lulu Huang, Qiang Wang, Heng Liu, Ye Cui, Yijun Tang, Peng Zhang, Chen Wang, Pinghui Feng.
Stimulator of interferon genes (STING, also known as MITA, ERIS or MPYS) induces the activation of TBK1 kinase and IRF3 transcription factor, upon sensing of microbial DNAs. How IRF3 is recruited onto the STING signalosome remains unknown. We report here that silencing of the ER adaptor SCAP markedly impairs the IRF3-responsive gene expression induced by STING. Scap knockdown mice are more susceptible to HSV-1 infection. Interestingly, SCAP translocates from ER, via Golgi, to perinuclear microsome in a STING-dependent manner. Mechanistically, the N-terminal transmembrane domain of SCAP interacts with STING, and the C-terminal cytosolic domain of SCAP binds to IRF3, thus recruiting IRF3 onto STING signalosome. Mis-localization of SCAP abolishes its antiviral function. Collectively, this study characterizes SCAP as an essential adaptor in the STING signaling pathway, uncovering a critical missing link in DNAs-triggered host antiviral responses.
Microbial infections represent an ever-present threat to host homeostasis and survival. The extracellular and intracellular microbes are dynamically and rapidly sensed by specific Pattern Recognition Receptors (PRRs), including TLRs, NLRs and RLRs [1–3]. Upon recognition of the conserved Pathogen Associated Molecular Patterns (PAMPs), PRRs initiate a myriad of signal transduction pathways, triggering innate and adaptive immune responses to eliminate the microbial pathogens [4,5].
Recent breakthroughs have characterized multiple cytosolic sensors that potentially monitor the cytosolic DNAs (cGAS, IFI16, DDX41, Mre11 and DNA-PKcs). STING is established unambiguously as the converging point of the DNA sensors, to further relay the activation signals on ER [31,32]. Notably, STING is induced to dimerize and traffic from the ER, via Golgi, to perinuclear microsome [6,23]. TBK1 is simultaneously recruited to the same compartment in a STING dependent manner, which then activates the transcription factor IRF3 . It is intriguing to dissect the molecular mechanisms of the DNA-driven assembly of the STING signalosome on either ER or the perinuclear microsome.