Mycobacterium tuberculosis MmsA (Rv0753c) Interacts with STING and Blunts the Type I Interferon Response

• Published in: mBio Vol. 11; no. 6
• Main Authors: Sun, Yifan, Zhang, Wei, Dong, Chunsheng, Xiong, Sidong
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.12.2020
• Subjects: Host-Microbe Biology; MmsA (Rv0753c); Mycobacterium tuberculosis; p62; selective autophagy; STING; type I IFN; MmsA (Rv0753c); STING; Mycobacterium tuberculosis; type I IFN; p62; selective autophagy
• ISSN: 2161-2129; 2150-7511
• DOI: 10.1128/mBio.03254-19

Type I interferon (IFN) plays an important role in persistence and disease pathogenesis. has evolved a number of mechanisms to evade host immune surveillance. However, it is unclear how the type I IFN response is tightly regulated by the determinants. Stimulator of interferon genes (STING) is an essential adaptor for type I IFN production triggered by genomic DNA or cyclic dinucleotides upon infection. To investigate how the type I IFN response is regulated by determinants, immunoprecipitation-mass spectrometry-based (IP-MS) proteomic analysis was performed to screen proteins interacting with STING in the context of infection. Among the many predicted candidates interacting with STING, the coding protein Rv0753c (MmsA) was identified. We confirmed that MmsA binds and colocalizes with STING, and the N-terminal regions of MmsA (amino acids [aa] 1 to 251) and STING (aa 1 TO 190) are responsible for MmsA-STING interaction. Type I IFN production was impaired with exogenous expression of MmsA in RAW264.7 cells. MmsA inhibited the STING-TBK1-IRF3 pathway, as evidenced by reduced STING levelS and subsequent IRF3 activation. Furthermore, MmsA facilitated p62-mediated STING autophagic degradation by binding p62 with its C terminus (aa 252 to 455), which may account for the negative regulation of MmsA in STING-mediated type I IFN production. Additionally, the R138W mutation, detected in a hypervirulent clinical isolate, enhanced the degradation of STING, implying the important relevance of MmsA in disease outcome. Together, we report a novel mechanism where MmsA serves as an antagonist of type I IFN response by targeting STING with p62-mediated autophagic degradation. It is unclear how the type I IFN response is regulated by mycobacterial determinants. Here, we characterized the previously unreported role of MmsA in immunological regulation of type I IFN response by targeting the central adaptor STING in the DNA sensing pathway. We identified STING-interacting MmsA by coimmunoprecipitation-mass spectrometry-based (IP-MS) proteomic analysis and showed MmsA interacting with STING and autophagy receptor p62 via its N terminus and C terminus, respectively. We also showed that MmsA downregulated type I IFN by promoting p62-mediated STING degradation. Moreover, the MmsA mutant R138W is potentially associated with the virulence of clinical strains owing to the modulation of STING protein. Our results provide novel insights into the regulatory mechanism of type I IFN response manipulated by mycobacterial MmsA and the additional cross talk between autophagy and STING in infection, wherein a protein from microbial pathogens induces autophagic degradation of host innate immune molecules.