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

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.

KEYWORDS:

• MERS-CoV
• nsp1
• autophagic flux
• mTOR
• lysosomes

Acknowledgements

We thank Zhengli Shi of the Wuhan Institute of Virology, Chinese Academy of Sciences, for sharing various MERS-CoV plasmids. We thank Xiao Wang (School of Pharmaceutical Sciences, Shandong University) for providing confocal laser-scanning (LSM 900 with Airyscan2), extracellular flux analysis (Seahorse XFe 24), and flow cytometer (BD FACS Celesta) testing.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials

Additional information

Funding

This work was supported by grant from the National Science and Technology Major Project of China (No.2018ZX10301401).