TRIM30α Is a Negative-Feedback Regulator of the Intracellular DNA and DNA Virus-Triggered 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 30 alpha (TRIM30 alpha) was induced by herpes simplex virus type 1 (HSV-1) infection in dendritic cells (DCs). Knockdown or genetic ablation of TRIM30 alpha augmented the type I IFNs and interleukin-6 response to intracellular DNA and DNA viruses. Trim30 alpha-deficient mice were more resistant to infection by DNA viruses. Biochemical analyses showed that TRIM30 alpha interacted with the stimulator of interferon genes (STING), which is a critical regulator of the DNA-sensing response. Overexpression of TRIM30 alpha promoted the degradation of STING via K48-linked ubiquitination at Lys275 through a proteasome-dependent pathway. These findings indicate that E3 ligase TRIM30 alpha is an important negative-feedback regulator of innate immune responses to DNA viruses by targeting STING.