ATM facilitates autophagy and protects against oxidative stress and apoptosis in response to ER stress in vitro

The endoplasmic reticulum (ER) responds to cellular stress by initiating an unfolded protein response (UPR) that mitigates misfolded protein accumulation by promoting protein degradation pathways. Chronic ER stress leads to UPR-mediated apoptosis and is a common underlying feature of various diseases, highlighting the modulators of the UPR as attractive targets for therapeutic intervention. Ataxia-telangiectasia mutated protein kinase (ATM) is a stress-responsive kinase that initiates autophagy in response to reactive oxygen species (ROS), and ATM deficiency is associated with increased ER stress markers in vitro. However, whether ATM participates in the UPR remains unclear. In this in vitro study, a novel role for ATM in the ER stress response is described using the well-characterized HEK293 cells treated with the common ER stress-inducing agent, tunicamycin, with and without the potent ATM inhibitor, KU-60019. We show for the first time that ATM is activated in a time-dependent manner downstream of UPR initiation in response to tunicamycin treatment. Furthermore, we demonstrate that ATM is required for p62-bound protein cargo degradation through the autophagy pathway in response to ER stress. Lastly, our data suggest a protective role for ATM in ER stress-mediated oxidative stress and mitochondrial apoptosis. Taken together, we highlight ATM as a potential novel drug target in ER stress-related diseases. [Display omitted] •ATM is activated downstream of the UPR.•ATM facilitates autophagy in response to ER stress.•ATM protects against ER stress-mediated oxidative stress.•ATM protects against ER stress-mediated apoptosis.