ABSTRACT

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 in vitro and in vivo. These findings clarify the mechanism by which MERS-CoV nsp1-mediated autophagy regulation, providing new insights for the prevention and treatment of the coronavirus.

摘要

自噬是一种细胞监视机制，在对抗入侵病原体方面发挥着重要作用。然而，病毒已经进化出各种策略来破坏自噬，甚至劫持它进行复制和释放。在这里，我们证明了中东呼吸综合征冠状病毒（MERS-CoV）非结构蛋白1（nsp1）诱导自噬但抑制自噬活性。MERS-CoV nsp1 表达增加细胞内 ROS 并降低 ATP 水平，从而激活 AMPK 并抑制 mTOR 信号通路，从而诱导自噬。同时，作为一种核酸内切酶，MERS-CoV nsp1 下调了富含 nsp1 颗粒的溶酶体相关基因的 mRNA，从而减少了溶酶体的生物合成和酸化，并抑制了自噬通量。重要的是，MERS-CoV nsp1 诱导的自噬可导致细胞死亡体外和体内。这些发现阐明了MERS-CoV nsp1介导的自噬调节机制，为冠状病毒的预防和治疗提供了新的见解。