Wang Junying, Wang Ling, Lu Wenting, Farhataziz Naser, Gonzalez Anastasia, Xing Junji, Zhang Zhiqiang
Immunobiology and Transplant Science Center, Department of Surgery, Houston Methodist Academic Institute, Houston Methodist, Houston, TX 77030, USA.
Immunobiology and Transplant Science Center, Department of Surgery, Houston Methodist Academic Institute, Houston Methodist, Houston, TX 77030, USA; Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, 130021, China.
Mucosal Immunol. 2025 Feb;18(1):135-150. doi: 10.1016/j.mucimm.2024.10.004. Epub 2024 Oct 11.
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 Ly6ACCR9CD4 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.
肠道病毒感染和肠道炎症被认为是致命性肠胃炎的主要病因，而NLRP6和NLRP9b信号通路控制着这些感染和炎症。然而，NLRP6和NLRP9b信号通路在肠道病毒感染中的调控机制仍未被探索。在本研究中，我们发现E3连接酶TRIM29在肠道上皮细胞（IECs）暴露于聚肌苷酸:聚胞苷酸（poly I:C）和肠道RNA病毒时，会抑制III型干扰素（IFN-λ）和白细胞介素-18（IL-18）的产生。在IECs中敲除TRIM29可有效限制由肠道RNA病毒、乳鼠中的轮状病毒以及成年小鼠中的脑心肌炎病毒（EMCV）引发的肠道炎症。炎症的减轻归因于IECs中IFN-λ和IL-18产生的增加，以及来自TRIM29缺陷小鼠的小肠中上皮内保护性Ly6ACCR9CD4 T细胞的更多募集。从机制上讲，TRIM29促进K48连接的泛素化，导致NLRP6和NLRP9b降解，从而使IECs分泌的IFN-λ和IL-18减少。我们的研究结果表明，肠道病毒利用TRIM29抑制IECs中的IFN-λ和炎性小体激活，从而促进病毒诱导的肠道炎症。这表明靶向TRIM29可能为缓解肠道疾病提供一种有前景的治疗策略。
