TRIM35 negatively regulates TLR7- and TLR9-mediated type I interferon production by targeting IRF7

•TRIM35 expression is induced by TLR7/9 ligand stimulation.•Knockdown of TRIM35 enhances type I IFN production following TLR7/9 stimulation.•TRIM35 interacts with IRF7 and induces the K48-linked ubiquitination of it.•TRIM35 promotes the degradation of IRF7 via a ubiquitin-proteasome pathway.

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.