Abstract：
Interferon (IFN) contributes to the host\'s antiviral response by inducing IFN-stimulated genes (ISGs). However, their functional targets and the mechanism of action remain elusive. Here, we report that one such ISG, TRIM21, interacts with and degrades the TRPV2 channel in myeloid cells, reducing its expression and providing host protection against viral infections. Moreover, viral infection upregulates TRIM21 in paracrine and autocrine manners, downregulating TRPV2 in neighboring cells to prevent viral spread to uninfected cells. Consistently, the Trim21-/- mice are more susceptible to HSV-1 and VSV infection than the Trim21+/+ littermates, in which viral susceptibility is rescued by inhibition or deletion of TRPV2. Mechanistically, TRIM21 catalyzes the K48-linked ubiquitination of TRPV2 at Lys295. TRPV2K295R is resistant to viral-infection-induced TRIM21-dependent ubiquitination and degradation, promoting viral infection more profoundly than wild-type TRPV2 when reconstituted into Lyz2-Cre;Trpv2fl/fl myeloid cells. These findings characterize targeting the TRIM21-TRPV2 axis as a conducive strategy to control viral spread to bystander cells.
摘要：
干扰素（IFN）通过诱导IFN刺激基因（ISGs）促进宿主的抗病毒反应。然而,他们的功能目标和作用机制仍然难以捉摸。这里,我们报告说，一个这样的ISG，TRIM21，与骨髓细胞中的TRPV2通道相互作用并降解，减少其表达并提供宿主对病毒感染的保护。此外，病毒感染以旁分泌和自分泌方式上调TRIM21，在邻近细胞中下调TRPV2以防止病毒传播到未感染细胞。始终如一，Trim21-/-小鼠比Trim21+/+同窝小鼠更容易感染HSV-1和VSV，其中通过抑制或缺失TRPV2挽救病毒易感性。机械上,TRIM21在Lys295处催化TRPV2的K48连接的泛素化。TRPV2K295R对病毒感染诱导的TRIM21依赖性泛素化和降解具有抗性，当重组为Lyz2-Cre;Trpv2fl/fl骨髓细胞时，比野生型TRPV2更严重地促进病毒感染。这些发现表征了靶向TRIM21-TRPV2轴作为控制病毒传播到旁观者细胞的有益策略。
