MERS-CoV nsp1 regulates autophagic flux via mTOR signalling and dysfunctional lysosomes

Autophagy, a cellular surveillance mechanism, plays an important role in combating invading pathogens. However, viruses have evolved various strategies to disrupt autophagy and even hijack it for replication and release. Here, we demonstrated that Middle East respiratory syndrome coronavirus (MERS-CoV) non-structural protein 1(nsp1) induces autophagy but inhibits autophagic activity. MERS-CoV nsp1 expression increased ROS and reduced ATP levels in cells, which activated AMPK and inhibited the mTOR signalling pathway, resulting in autophagy induction. Meanwhile, as an endonuclease, MERS-CoV nsp1 downregulated the mRNA of lysosome-related genes that were enriched in nsp1-located granules, which diminished lysosomal biogenesis and acidification, and inhibited autophagic flux. Importantly, MERS-CoV nsp1-induced autophagy can lead to cell death <i>in vitro</i> and <i>in vivo</i>. These findings clarify the mechanism by which MERS-CoV nsp1-mediated autophagy regulation, providing new insights for the prevention and treatment of the coronavirus.

自噬（Autophagy）作为一种细胞监视机制，在抵御入侵病原体的过程中发挥着关键作用。然而，病毒已演化出多种策略以破坏自噬，甚至劫持该过程完成自身复制与释放。本研究证实，中东呼吸综合征冠状病毒（Middle East respiratory syndrome coronavirus, MERS-CoV）的非结构蛋白1（non-structural protein 1, nsp1）可诱导自噬，但会抑制自噬活性。MERS-CoV nsp1的表达会提升细胞内活性氧（Reactive Oxygen Species, ROS）水平并降低三磷酸腺苷（Adenosine Triphosphate, ATP）含量，进而激活腺苷酸活化蛋白激酶（AMP-activated protein kinase, AMPK）并抑制哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin, mTOR）信号通路，最终诱导自噬。与此同时，作为核酸内切酶的MERS-CoV nsp1可下调定位于nsp1颗粒中的溶酶体相关基因的mRNA水平，从而削弱溶酶体生物发生与酸化过程，抑制自噬流。尤为重要的是，MERS-CoV nsp1诱导的自噬可在体外（in vitro）和体内（in vivo）环境中引发细胞死亡。本研究结果阐明了MERS-CoV nsp1介导的自噬调控机制，为冠状病毒的预防与治疗提供了全新的研究视角。