Dr. Xuetao Cao’s group identifies a novel lncRNA which promotes antiviral innate immunity


The innate immune response provides the first line of host defense against invading pathogens. Upon recognizing the infection, pattern recognition receptors (PRRs) are activated and transduct the signal through antiviral kinase TANK-binding kinase 1 (TBK1), which mediates the activation of interferon regulatory factor 3 (IRF3) and induces the production of type I IFN (IFN-I) in virus-infected cells. The production of IFN-I must be controlled precisely. Therefore, the mechanism behind the activation or suppression of innate immunity is one of the most important research fields in immunology. Post-translational modifications (PTMs) such as phosphorylation, acetylation, ubiquitination and glycosylation of sensors and downstream signaling molecules play significant roles in the activation or repression of innate immune response. Long non-coding RNAs have been reported to interact with proteins and control the PTM in immune cell differentiation and development. However, the function of lncRNAs in antiviral immune response remains largely unknown.

On Dec 15, 2020, Xuetao Cao’s Group published a paper entitled “Decreased Expression of the Host Long-Noncoding RNA-GM Facilitates Viral Escape by Inhibiting the Kinase activity TBK1 via S-glutathionylation” in Immunity. Dr. Yujia Wang from Zhejiang University is the first author.

In this study, the authors identified lncRNA-GM as a GSH-modification-related lncRNA that promoted TBK1 kinase activity and IFN-I production. Various viruses could suppress the expression of lncRNA-GM and evade immune elimination. Using Chromatin Isolation by RNA Purification (ChIRP) approach, the authors identified that Glutathione S-transferase M1 (GSTM1) bound to lncRNA-GM. And GSTM1 could mediate S-glutathionylation on Cys 637 of TBK1 while lncRNA-GM was down-regulated, which dampened TBK1 kinase activity. Through metabolism test, the authors found that infection induced glutathione metabolic reprogramming could promote GSTM-dependent TBK1 inactivation.

In conclusion, Cao’s group identified a novel lncRNA that promoted IFN-I production by inhibiting S-glutathionylation of TBK1 through direct binding to GSTM1 and thus enhancing TBK1 kinase activity. Upon viral infection, lncRNA-GM expression was suppressed, leading to increased S-glutathionylation level, reduction of TBK1 kinase activity and impaired the antiviral innate response. The study provides new way of viral evasion of immunological elimination by virus infection-mediated downregulation of the antiviral lncRNA. In addition, the data provided mechanistic insight into how glutathione promotes virus survival and immune escape.