Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, 156 McElroy Hall, Stillwater, OK 74078, USA.
Department of Microbiology and Immunology, Tulane University, New Orleans, LA 70112, USA.
Viruses. 2020 Jan 22;12(2):131. doi: 10.3390/v12020131.
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.
水疱性口炎病毒（VSV）是一种动物源性的、负链 RNA 病毒，属于 Rhabdoviridae 科。VSV 的核蛋白（N）保护病毒基因组 RNA，并在病毒转录和复制中发挥重要作用，这使得核蛋白成为宿主防御的理想靶点。然而，宿主固有/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。在本研究中，我们发现 VSV 的 N 蛋白（VSV-N）与一种泛素 E3 连接酶，即三肽基结构域蛋白 41（TRIM41）相互作用。TRIM41 的过表达抑制了 VSV 的感染。相反，TRIM41 的耗尽增加了宿主对 VSV 的易感性。此外，TRIM41 的 E3 连接酶缺陷突变体未能限制 VSV 的感染，表明 TRIM41 在病毒限制中的 E3 连接酶活性是必需的。事实上，TRIM41 在细胞和体外泛素化了 VSV-N。TRIM41 介导的泛素化导致 VSV-N 通过蛋白酶体降解，从而限制了 VSV 的感染。总之，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，确定 TRIM41 是一种针对 VSV 的新的固有免疫因子。
