The Functional Study Of TRIM In DNA Virus Infection-Triggered Immune Response And TLR Signaling

The innate immune system is the first barrier of defense against pathogens. Host cell utilizes the germline-encoded pattern recognition receptors (PRRs) to sense pathogen-associated molecular patterns (PAMPs) of microbes. Activated PRRs will induce the downstream immune response, such as the production of interferons, inflammatory cytokines or chemokines, and so on. The RING domain-containing members-tripartite motif-containing (TRIM) superfamily plays important role in regulation of innate immune signaling pathway. Based on our study, we focus on the role of two members-TRIM30a and TRIM35, which negatively regulate DNA virus-triggered immune response and TLR signaling, respectively.1. TRIM30a negatively regulates DNA virues-triggered immune response by targeting STING.Uncontrolled immune responses to intracellular DNA have been shown to induce autoimmune diseases. Homeostasis regulation of immune responses to cytosolic DNA is critical for limiting the risk of autoimmunity and survival of the host. Here, we report that the E3 ubiquitin ligase tripartite motif protein 30a (TRIM30a) was induced by herpes simplex virus type 1 (HSV-1) infection in dendritic cells (DCs). Knockdown or genetic ablation of TRIM30a augmented the type I IFNs and interleukin-6 response to intracellular DNA and DNA viruses.Trim30α-deficient mice were more resistant to infection by DNA viruses. Biochemical analyses showed that TRIM30a interacted with the stimulator of interferon genes (STING), which is a critical regulator of the DNA-sensing response. Overexpression of TRIM30a promoted the degradation of STING via K48-linked ubiquitination at Lys275 through a proteasome-dependent pathway. These findings indicate that E3 ligase TRIM30a is an important negative-feedback regulator of innate immune responses to DNA viruses by targeting STING.2. TRIM35 negatively regulates TLR7-and TLR9-mediated type I interferon production by targeting IRF7.Toll-like receptor 7 (TLR7) and TLR9 sense viral nucleic acids and induce type I IFN production, which must be properly controlled to avoid autoimmune diseases. Here, we report the negative regulation of TLR7/9-mediated type I IFN production by TRIM35. TRIM35 expression is induced by TLR7/9 stimulation and then interacts with IRF7, which is the master regulator of type I IFN response. Furthermore, TRIM35 promotes the K48-linked ubiquitination of IRF7 and induces its degradation via a proteasome-dependent pathway. Therefore, TRIM35 is a negative feedback regulator of TLR7/9-mediated type I IFN production due to its ability to suppress the stability of IRF7.In summary, our research indicates that TRIM30a and TRIM35 are E3 ligases and act as important negative-feedback regulators in DNA virues-triggered immune response and TLR7/9 immune pathway, respectively. They play critical role in defensing against autoimmunity and maintaining homeostasis.