Abstract
Under RNA virus infection, retinoic acid-inducible gene I (RIG-I) in host cells recognizes viral RNA and activates the expression of type I IFN. To investigate the roles of protein methyltransferases and demethylases in RIG-I antiviral signaling pathway, we screened all the known related enzymes with a siRNA library and identified LSD1 as a positive regulator for RIG-I signaling. Exogenous expression of LSD1 enhances RIG-I signaling activated by virus stimulation, whereas its deficiency restricts it. LSD1 interacts with RIG-I, promotes its K63-linked polyubiquitination and interaction with VISA/MAVS. Interestingly, LSD1 exerts its function in antiviral response not dependent on its demethylase activity but through enhancing the interaction between RIG-I with E3 ligases, especially TRIM25. Furthermore, we provide in vivo evidence that LSD1 increases antiviral gene expression and inhibits viral replication. Taken together, our findings demonstrate that LSD1 is a positive regulator of signaling pathway triggered by RNA-virus through mediating RIG-I polyubiquitination.
Highlights
Innate immunity is the first barrier against pathogen invasion, such as viruses and bacteria [1,2,3]
retinoic acid–inducible gene I (RIG-I) signaling pathway is critical for human cells to defend from RNA virus infection, such as SARS-CoV-2, influenza virus, and Vesicular Stomatitis Virus (VSV)
The current study reveals a novel function of LSD1 in regulating the activation of RIG-I signaling pathway
Summary
Innate immunity is the first barrier against pathogen invasion, such as viruses and bacteria [1,2,3]. Pathogens are recognized by specific pattern recognition receptors, which induce a cascade of immune responses, and eliminated by interferons and cytokines [4,5]. Several families of pattern recognition receptors have been identified, including Toll-like receptors (TLRs), retinoic acid–inducible gene I (RIG-I)–like receptors (RLRs), cyclic GMP–AMP synthase (cGAS) like receptors, NOD-like receptors, and C-type lectin receptors [2,3]. RNA viruses, such as Sendai virus (SeV) and vesicular stomatitis virus (VSV), are recognized by RLRs when infecting cells. RIG-I, melanoma differentiation-associated gen 5 (MDA5) and DExHbox helicase 58 (DHX58, known as LGP2) are three types of RLRs, and they all belong to the DEA(D/H) box RNA helicase family [6,7]. Activated VISA/MAVS promotes phosphorylation of TANK binding kinase 1 (TBK1) and the subsequent phosphorylation of interferon regulatory factor 3 (IRF3). Phosphorylated IRF3 enters nucleus to turn on the expression of type I interferons [4,6,7,11,12,13,14,15,16,17,18]
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