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2023年4月，天津大學(xué)生命科學(xué)學(xué)院，國家病毒性疾病預(yù)防控制研究所，病原體與生物安全國家重點實驗室，軍事醫(yī)學(xué)科學(xué)院北京微生物與流行病學(xué)研究所，天津大學(xué)環(huán)境科學(xué)與工程學(xué)院，天津市生物大分子結(jié)構(gòu)功能與應(yīng)用重點實驗室(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老師研究團隊在《Journal of Virology》上發(fā)表論文：

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

“SFTSV非結(jié)構(gòu)蛋白通過與Vimentin相互作用誘導(dǎo)自噬促進(jìn)病毒復(fù)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：

發(fā)熱伴血小板減少綜合征病毒(SFTSV)是一種新發(fā)現(xiàn)的與人類嚴(yán)重出血熱相關(guān)的靜脈病毒。研究表明SFTSV核蛋白(N)誘導(dǎo)becn1依賴性自噬，促進(jìn)病毒組裝和釋放。然而，其他SFTSV蛋白在調(diào)節(jié)自噬中的功能尚未報道。在這項研究中，研究人員鑒定了SFTSV NSs，一種在感染細(xì)胞的細(xì)胞質(zhì)中形成病毒質(zhì)樣結(jié)構(gòu)的非結(jié)構(gòu)蛋白，作為介導(dǎo)SFTSV誘導(dǎo)的自噬的病毒成分。研究人員發(fā)現(xiàn)SFTSV NSs誘導(dǎo)的自噬是不依賴包涵體的，大多數(shù)phenuivirus NSs具有自噬誘導(dǎo)作用。與N蛋白誘導(dǎo)的自噬不同，SFTSV NSs通過不依賴包涵體的方式與宿主的vimentin相互作用，是調(diào)節(jié)自噬的關(guān)鍵。NSs通過k48連接的泛素-蛋白酶體途徑與波形蛋白相互作用并誘導(dǎo)波形蛋白降解。這種負(fù)調(diào)節(jié)Beclin1-vimentin復(fù)合物形成并促進(jìn)自噬。此外，研究人員鑒定了vimentin的NSs結(jié)合域，發(fā)現(xiàn)野生型vimentin過表達(dá)可拮抗NSs誘導(dǎo)的自噬作用，抑制病毒復(fù)制，提示vimentin是一個潛在的抗病毒靶點。本研究揭示了SFTSV非結(jié)構(gòu)蛋白激活自噬的新機制，為NSs在SFTSV感染和發(fā)病機制中的作用提供了新的認(rèn)識。

該論文中，HeLa細(xì)胞和293T細(xì)胞的體外培養(yǎng)是使用Ausbian特級胎牛血清完成的。