Vesicular stomatitis virus (VSV) is a zoonotic, negative-stranded RNA virus of the family Rhabdoviridae. The nucleoprotein (N) of VSV protects the viral genomic RNA and plays an essential role in viral transcription and replication, which makes the nucleoprotein an ideal target of host defense. However, whether and how host innate/intrinsic immunity limits VSV infection by targeting the N protein are unknown. In this study, we found that the N protein of VSV (VSV-N) interacted with a ubiquitin E3 ligase, tripartite motif protein 41 (TRIM41). Overexpression of TRIM41 inhibited VSV infection. Conversely, the depletion of TRIM41 increased host susceptibility to VSV. Furthermore, the E3 ligase defective mutant of TRIM41 failed to limit VSV infection, suggesting the requirement of the E3 ligase activity of TRIM41 in viral restriction. Indeed, TRIM41 ubiquitinated VSV-N in cells and in vitro. TRIM41-mediated ubiquitination leads to the degradation of VSV-N through proteasome, thereby limiting VSV infection. Taken together, our study identifies TRIM41 as a new intrinsic immune factor against VSV by targeting the viral nucleoprotein for ubiquitination and subsequent protein degradation.

中文翻译：

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TRIM41介导的核蛋白泛素化限制了水泡性口腔炎病毒感染。

水泡性口腔炎病毒（VSV）是Rhabdoviridae家族的一种人畜共患的负链RNA病毒。VSV的核蛋白（N）保护病毒基因组RNA，并在病毒的转录和复制中起重要作用，这使该核蛋白成为宿主防御的理想靶标。但是，宿主先天/内在免疫是否以及如何通过靶向N蛋白来限制VSV感染尚不清楚。在这项研究中，我们发现VSV的N蛋白（VSV-N）与泛素E3连接酶三方基序蛋白41（TRIM41）相互作用。TRIM41的过表达抑制了VSV感染。相反，TRIM41的耗尽增加了宿主对VSV的敏感性。此外，TRIM41的E3连接酶缺陷型突变体不能限制VSV感染，提示病毒限制中需要TRIM41的E3连接酶活性。确实，TRIM41在细胞内和体外泛素化了VSV-N。TRIM41介导的泛素化作用通过蛋白酶体导致VSV-N降解，从而限制了VSV感染。综上所述，我们的研究通过靶向病毒核蛋白进行泛素化和随后的蛋白降解，将TRIM41鉴定为针对VSV的新的内在免疫因子。