Abstract
Innate immune system is armed by several lines of pattern recognition receptors to sense various viral infection and to initiate antiviral immune response. This process is under a tight control and the negative feedback induced by infection and/or inflammation is critical to maintain immune homoeostasis and to prevent autoimmune disorders, however, the molecular mechanism is not fully understood. Here we report TRIM29, a ubiquitin E3 ligase, functions as an inducible negative regulator of innate immune response triggered by DNA virus and cytosolic DNA. DNA virus and cytosolic DNA stimulation induce TRIM29 expression robustly in macrophages and dendritic cells, although the basal level of TRIM29 is undetectable in those cells. TRIM29 deficiency elevates IFN-I and proinflammatory cytokine production upon viral DNA and cytosolic dsDNA stimulation. Consistently, in vivo experiments show that TRIM29-deficient mice are more resistant to HSV-1 infection than WT controls, indicated by better survival rate and reduced viral load in organs. Mechanism studies suggest that STING–TBK1–IRF3 signaling pathway in TRIM29 KO cells is significantly enhanced and the degradation of STING is impaired. Furthermore, we identify that TRIM29 targets STING for K48 ubiquitination and degradation. This study reveals TRIM29 as a crucial negative regulator in immune response to DNA virus and cytosolic DNA, preventing potential damage caused by overcommitted immune responses.
Highlights
Antiviral immunity is initiated by the recognition of virus-derived nuclear acids via germline-encoded pattern recognition receptors (PRRs) of innate immune cells, which activates downstream signal pathways leading to production of type I interferon-I (IFN-I) and proinflammatory cytokine[1]
TRIM29 is induced by cytosolic double-strand DNA (dsDNA) stimulation TRIM29 is recently reported to express highly in alveolar macrophage (AM), which plays an nonredundant role in host defense against Haemophilus influenza infection and lipopolysaccharide (LPS) induced septic shock, as well as RNA virus infection[29]
As the TRIM29 expression level is very low in the unstimulated macrophage or dendritic cell (DC)[29], we first examined whether TRIM29 expression level was induced by PAMP molecules, especially the pathogen-associated molecular pattern (PAMP) molecules derived from virus
Summary
Antiviral immunity is initiated by the recognition of virus-derived nuclear acids via germline-encoded pattern recognition receptors (PRRs) of innate immune cells, which activates downstream signal pathways leading to production of type I interferon-I (IFN-I) and proinflammatory cytokine[1]. Many sensors of DNA have been discovered, among which TLR9 is the first identified DNA sensor for bacterial unmethylated CpG DNA in endosome[8]; cytosolic DNA is recognized by absent in melanoma 2 (AIM2)[9], DNA-dependent activator of IFN regulator factors (DAI)[10], RNA polymerase III11, IFNgamma inducible factor 16 (IFI16)[12], DDX4113, DNAdependent protein kinase (DNA-PK)[14] and cyclic-GMPAMP (cGAMP) synthase (cGAS)[15,16]. Most of identified DNA sensors bind DNA and trigger IFN-I production, except AIM2 that induces inflammasome activation and IL-1β and IL-18 maturation[9]. IFI16 is the only DNA sensor that has the capacity to induce both inflammasome activation and IFN-I production[19,20]
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