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

Area of Science:

• Virology
• Cell Biology
• Molecular Biology

Background:

• Autophagy is a crucial cellular process for pathogen defense.
• Viruses often manipulate autophagy for their own replication and spread.
• Understanding viral interference with autophagy is key to developing antivirals.

Purpose of the Study:

• To elucidate the mechanism by which MERS-CoV nsp1 affects autophagy.
• To investigate the consequences of MERS-CoV nsp1-induced autophagy on host cells.
• To identify potential therapeutic targets for MERS-CoV infection.

Main Methods:

• Assessing autophagy induction and inhibition by MERS-CoV nsp1.
• Measuring reactive oxygen species (ROS) and ATP levels.
• Analyzing AMPK and mTOR signaling pathways.
• Evaluating lysosomal gene expression and function.
• Investigating MERS-CoV nsp1-induced cell death in vitro and in vivo.

Main Results:

• MERS-CoV nsp1 induced autophagy by activating AMPK and inhibiting mTOR signaling via increased ROS and reduced ATP.
• MERS-CoV nsp1, acting as an endonuclease, downregulated lysosomal genes, impairing lysosomal biogenesis and acidification.
• This disruption inhibited autophagic flux and led to significant cell death.
• MERS-CoV nsp1-mediated autophagy dysregulation was confirmed both in vitro and in vivo.

Conclusions:

• MERS-CoV nsp1 manipulates cellular autophagy, inducing it while simultaneously inhibiting its degradative capacity.
• The impaired autophagic flux and subsequent cell death present a novel mechanism of MERS-CoV pathogenesis.
• Targeting MERS-CoV nsp1-mediated autophagy offers a promising strategy for coronavirus treatment.