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SFTSV非結構蛋白通過與Vimentin相互作用誘導自噬促進病毒復制

更新時間:2024-09-30  |  點擊率:445

20234月,天津大學生命科學學院,國家病毒性疾病預防控制研究所,病原體與生物安全國家重點實驗室,軍事醫(yī)學科學院北京微生物與流行病學研究所,天津大學環(huán)境科學與工程學院,天津市生物大分子結構功能與應用重點實驗室(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非結構蛋白通過與Vimentin相互作用誘導自噬促進病毒復制"


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)的與人類嚴重出血熱相關的靜脈病毒。研究表明SFTSV核蛋白(N)誘導becn1依賴性自噬,促進病毒組裝和釋放。然而,其他SFTSV蛋白在調節(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,一種在感染細胞的細胞質中形成病毒質樣結構的非結構蛋白,作為導SFTSV誘導的自噬的病毒成分。研究人員發(fā)現(xiàn)SFTSV NSs誘導的自噬是不依賴包涵體的,大多數phenuivirus NSs具有自噬誘導作用。與N蛋白誘導的自噬不同,SFTSV NSs通過不依賴包涵體的方式與宿主的vimentin相互作用,是調節(jié)自噬的關鍵。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波形蛋白降解。這種負調節(jié)Beclin1-vimentin復合物形成并促進自噬。此外,研究人員鑒定了vimentin的NSs結合域,發(fā)現(xiàn)野生型vimentin過表達可拮抗NSs誘導的自噬作用,抑制病毒復制,提示vimentin是一個潛在的抗病毒靶點。本研究揭示了SFTSV非結構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識。


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