2023年4月，天津大学生命科学学院，国家病毒性疾病预防控制研究所，病原体与生物安全国家重点实验室，军事医学科学院北京微生物与流行病学研究所，天津大学环境科学与工程学院，天津市生物大分子结构功能与应用重点实验室(School of Life Sciences, Tianjin University, Tianjin, China；National Institute for Viral Disease Control and Prevention, CDC, Beijing, China；State Key Laboratory of Pathogen and Biosecurity Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China；School of Environmental Science and Engineering, Tianjin University, Tianjin, China；Institute of Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, Tianjin, China) Yazhi Su老师研究团队在《Journal of Virology》上发表论文：

“The SFTSV Nonstructural Proteins Induce Autophagy to Promote Viral Replication via Interaction with Vimentin”

“SFTSV非结构蛋白通过与Vimentin相互作用诱导自噬促进病毒复制”

Abstract：

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly identified phlebovirus associated with severe hemorrhagic fever in humans. Studies have shown that SFTSV nucleoprotein (N) induces BECN1-dependent autophagy to promote viral assembly and release. However, the function of other SFTSV proteins in regulating autophagy has not been reported. In this study, we identify SFTSV NSs, a nonstructural protein that forms viroplasm-like structures in the cytoplasm of infected cells as the virus component mediating SFTSV-induced autophagy. We found that SFTSV NSs-induced autophagy was inclusion body independent, and most phenuivirus NSs had autophagy-inducing effects. Unlike N protein-induced autophagy, SFTSV NSs was key in regulating autophagy by interacting with the host's vimentin in an inclusion body-independent manner. NSs interacted with vimentin and induced vimentin degradation through the K48-linked ubiquitin-proteasome pathway. This negatively regulating Beclin1-vimentin complex formed and promoted autophagy. Furthermore, we identified the NSs-binding domain of vimentin and found that overexpression of wild-type vimentin antagonized the induced effect of NSs on autophagy and inhibited viral replication, suggesting that vimentin is a potential antiviral target. The present study shows a novel mechanism through which SFTSV nonstructural protein activates autophagy, which provides new insights into the role of NSs in SFTSV infection and pathogenesis. IMPORTANCE Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly emerging tick-borne pathogen that causes multifunctional organ failure and even death in humans. As a housekeeping mechanism for cells to maintain steady state, autophagy plays a dual role in viral infection and the host's immune response. However, the relationship between SFTSV infection and autophagy has not been described in detail yet. Here, we demonstrated that SFTSV infection induced complete autophagic flux and facilitated viral proliferation. We also identified a key mechanism underlying NSs-induced autophagy, in which NSs interacted with vimentin to inhibit the formation of the Beclin1-vimentin complex and induced vimentin degradation through K48-linked ubiquitination modification. These findings may help us understand the new functions and mechanisms of NSs and may aid in the identification of new antiviral targets.

摘要：

发热伴血小板减少综合征病毒(SFTSV)是一种新发现的与人类严重出血热相关的静脉病毒。研究表明SFTSV核蛋白(N)诱导becn1依赖性自噬，促进病毒组装和释放。然而，其他SFTSV蛋白在调节自噬中的功能尚未报道。在这项研究中，研究人员鉴定了SFTSV NSs，一种在感染细胞的细胞质中形成病毒质样结构的非结构蛋白，作为介导SFTSV诱导的自噬的病毒成分。研究人员发现SFTSV NSs诱导的自噬是不依赖包涵体的，大多数phenuivirus NSs具有自噬诱导作用。与N蛋白诱导的自噬不同，SFTSV NSs通过不依赖包涵体的方式与宿主的vimentin相互作用，是调节自噬的关键。NSs通过k48连接的泛素-蛋白酶体途径与波形蛋白相互作用并诱导波形蛋白降解。这种负调节Beclin1-vimentin复合物形成并促进自噬。此外，研究人员鉴定了vimentin的NSs结合域，发现野生型vimentin过表达可拮抗NSs诱导的自噬作用，抑制病毒复制，提示vimentin是一个潜在的抗病毒靶点。本研究揭示了SFTSV非结构蛋白激活自噬的新机制，为NSs在SFTSV感染和发病机制中的作用提供了新的认识。

该论文中，HeLa细胞和293T细胞的体外培养是使用Ausbian特级胎牛血清完成的。