自噬正在成为宿主防御多种感染的关键参与者,除了其保守的功能,以维持细胞内稳态。引人注目的是,一些病原体已经进化出逃避的策略,颠覆或利用自噬途径的不同步骤来实现其生命周期。这里,我们提出了一种新的操纵自噬的病毒机制,以使自身受益于严重发热伴血小板减少综合征布尼亚病毒(SFTSV,一种新兴的高致病性病毒)作为一种模式。SFTSV感染引发自噬,导致完全的自噬通量。机械上,我们表明SFTSV(NSs)的非结构蛋白与mTOR相互作用,自噬的关键调节因子,通过靶向其激酶结构域并将mTOR捕获到由NS本身诱导的病毒包涵体(IBs)中。此外,NSsimprepairsmTOR在Ser757上介导的unc-51样激酶1(ULK1)磷酸化,破坏mTOR对ULK1活性的抑制作用,从而促进自噬诱导。药物治疗和Beclin-1基因敲除实验结果证明,反过来,自噬增强SFTSV感染和传播。此外,小基因组报告系统显示SFTSV核糖核蛋白(转录和复制机制)活性可以通过自噬来增强。此外,我们发现与SFTSV相关的布尼亚病毒的NSs蛋白具有靶向mTOR的保守功能。一起来看,我们揭示了通过与mTOR相互作用诱导病毒自噬的病毒策略,将mTOR隔离到IBs中,从而激发下游ULK1途径,这为病毒操纵自噬提供了新的范例,并可能有助于为将来开发针对SFTSV和相关病原体的特定抗病毒疗法提供信息。
Autophagy is emerging as a critical player in host defense against diverse infections, in addition to its conserved function to maintain cellular homeostasis. Strikingly, some pathogens have evolved strategies to evade, subvert or exploit different steps of the autophagy pathway for their lifecycles. Here, we present a new viral mechanism of manipulating autophagy for its own benefit with severe fever with thrombocytopenia syndrome bunyavirus (SFTSV, an emerging high-pathogenic virus) as a model. SFTSV infection triggers autophagy, leading to complete autophagic flux. Mechanistically, we show that the nonstructural protein of SFTSV (NSs) interacts with mTOR, the pivotal regulator of autophagy, by targeting its kinase domain and captures mTOR into viral inclusion bodies (IBs) induced by NSs itself. Furthermore, NSsimpairs mTOR-mediated phosphorylation of unc-51-like kinase 1 (ULK1) at Ser757, disrupting the inhibitory effect of mTOR on ULK1 activity and thus contributing to autophagy induction. Pharmacologic treatment and Beclin-1 knockout experimental results establish that, in turn, autophagy enhances SFTSV infection and propagation. Moreover, the minigenome reporter system reveals that SFTSV ribonucleoprotein (the transcription and replication machinery) activity can be bolstered by autophagy. Additionally, we found that the NSs proteins of SFTSV-related bunyaviruses have a conserved function of targeting mTOR. Taken together, we unravel a viral strategy of inducing pro-viral autophagy by interacting with mTOR, sequestering mTOR into IBs and hence provoking the downstream ULK1 pathway, which presents a new paradigm for viral manipulation of autophagy and may help inform future development of specific antiviral therapies against SFTSV and related pathogens.