Snf1 AMPK positively regulates ER-phagy via expression control of Atg39 autophagy receptor in yeast ER stress response

Author summary All organisms are exposed to harmful environmental factors, for example, ultraviolet light, heat, and chemical compounds. These factors produce defective proteins within the cells both directly and indirectly by inducing genetic mutations. The endoplasmic reticulum (ER) is one of the cellular compartments and responsible for quality control of secretory and membrane proteins. The condition where defective secretory and membrane proteins accumulate in the ER is called ER stress. In human, ER stress is implicated in a variety of diseases, such as diabetes, cancers and neuro-degenerative diseases, including Alzheimer's disease and Parkinson's disease. To clear defective proteins in the ER, cell actuates the defense mechanism referred to as ER stress response. ER stress response is evolutionarily conserved among eukaryotic cells from yeast to human. Here, we investigate the mechanism by which ER stress induces ER-phagy, selective autophagic degradation of the ER, using the budding yeast as a model cell. We demonstrate the molecular link between the stress-responsive kinase, the transcriptional factors, gene expression of the autophagy-related gene and ER stress-induced ER-phagy. Autophagy is a fundamental process responsible for degradation and recycling of intracellular contents. In the budding yeast, non-selective macroautophagy and microautophagy of the endoplasmic reticulum (ER) are caused by ER stress, the circumstance where aberrant proteins accumulate in the ER. The more recent study showed that protein aggregation in the ER initiates ER-selective macroautophagy, referred to as ER-phagy; however, the mechanisms by which ER stress induces ER-phagy have not been fully elucidated. Here, we show that the expression levels ofATG39, encoding an autophagy receptor specific for ER-phagy, are significantly increased under ER-stressed conditions.ATG39upregulation in ER stress response is mediated by activation of its promoter, which is positively regulated by Snf1 AMP-activated protein kinase (AMPK) and negatively by Mig1 and Mig2 transcriptional repressors. In response to ER stress, Snf1 promotes nuclear export of Mig1 and Mig2. Our results suggest that during ER stress response, Snf1 mediates activation of theATG39promoter and consequently facilitates ER-phagy by negatively regulating Mig1 and Mig2.