Alleviating chronic ER stress by p38-Ire1-Xbp1 pathway and insulin-associated autophagy in C. elegans neurons

ER stress occurs in many physiological and pathological conditions. However, how chronic ER stress is alleviated in specific cells in an intact organism is an outstanding question. Here, overexpressing the gap junction protein UNC-9 (Uncoordinated) in C. elegans neurons triggers the Ire1-Xbp1-mediated stress response in an age-dependent and cell-autonomous manner. The p38 MAPK PMK-3 acts upon the phosphorylation of IRE-1 to regulate chronic stress. Overexpressing gap junction protein also activates autophagy and the insulin pathway functions through autophagy, but not the transcription of genes encoding ER chaperones, to counteract the p38-Ire1-Xbp1-mediated stress response. Together, these results reveal an intricate cellular regulatory network in response to chronic stress in a subset of cells in multicellular organism. Author SummaryThe accumulation of unfolded proteins triggers the ER stress response (UPR), which allows cells to fight against fluctuations in protein expression under both physiological and pathological conditions. Severe acute ER stress responses can be induced by drug treatment. However, such intense ER stress rarely occurs ubiquitously in every cell type in vivo. Here, we designed a genetic system in the nematode C. elegans, which allows us to induce ER stress in specific cells, without drug treatment or any other external stimuli, and then to monitor the stress response. Using this system, genetic screens identified that the p38 MAPK directly acts through the IRE-1-XBP-1 branch of the UPR to promote the stress response. Meanwhile, the insulin receptor functions through autophagy activation to counteract the p38-IRE-1-XBP-1 pathway. Together, these results reveal an intricate cellular regulatory network in response to chronic stress in multicellular organism.