TRIM29 controls enteric RNA virus-induced intestinal inflammation by targeting NLRP6 and NLRP9b signaling pathways

Infections by enteric virus and intestinal inflammation are recognized as a leading cause of deadly gastroenteritis, and NLRP6 and NLRP9b signaling control these infection and inflammation. However, the regulatory mechanisms of the NLRP6 and NLRP9b signaling in enteric viral infection remain unexplored. In this study, we found that the E3 ligase TRIM29 suppressed type III interferon (IFN-λ) and interleukin-18 (IL-18) production by intestinal epithelial cells (IECs) when exposed to polyinosinic:polycytidylic acid (poly I:C) and enteric RNA viruses. Knockout of TRIM29 in IECs was efficient to restrict intestinal inflammation triggered by the enteric RNA viruses, rotavirus in suckling mice, and the encephalomyocarditis virus (EMCV) in adults. This attenuation in inflammation was attributed to the increased production of IFN-λ and IL-18 in the IECs and more recruitment of intraepithelial protective Ly6A⁺CCR9⁺CD4⁺ T cells in small intestines from TRIM29-deficient mice. Mechanistically, TRIM29 promoted K48-linked ubiquitination, leading to the degradation of NLRP6 and NLRP9b, resulting in decreased IFN-λ and IL-18 secretion by IECs. Our findings reveal that enteric viruses utilize TRIM29 to inhibit IFN-λ and inflammasome activation in IECs, thereby facilitating viral-induced intestinal inflammation. This indicates that targeting TRIM29 could offer a promising therapeutic strategy for alleviating gut diseases.