Abstract

The accumulation of misfolded and unfolded proteins within the endoplasmic reticulum (ER) lumen induces ER stress, which in turn triggers various consequences, such as the unfolded protein response (UPR). AMP-activated protein kinase (AMPK) is also a cellular stress sensor. However, the interplay between AMPK and ER stress remains poorly understood. In this study, we report that in the fission yeast Schizosaccharomyces pombe , the deletion of erd2 , a central component for the retrieval of ER-resident proteins, leads to the accumulation of the canonical ER luminal chaperone Bip1 in the cytosol. Moreover, we demonstrate that erd2 deletion increases the levels of the AMPK upstream kinase Ssp1 in a Bip1-dependent manner, thereby promoting AMPK phosphorylation. Intriguingly, although these phenotypes are not dependent on UPR, they can also be caused by ER stress. We further identify multiple E3 ubiquitin ligases that are responsible for the regulation of Ssp1 stability, and Bip1 physically interacts with and stabilises Ssp1 by inhibiting ubiquitination of Ssp1. Additionally, we elucidate that AMPK activation, mediated by the stabilised Ssp1, is required to sustain cell viability, particularly in cells lacking Erd2. Collectively, our findings demonstrate the important role of Erd2 in the maintenance of cellular homeostasis and establish a link between ER stress and AMPK signalling.