Phosphatidylcholine coordinates ER-autonomous and ER-nonautonomous adaptations to unfolded protein response dysfunction

作者：Haixiang Tong, Wei Li, Pangui Yuan, Xinyu Wang, Shanshan Pang, Haiqing Tang · 发表于：Journal of Biological Chemistry · 年份：2025 · DOI：10.1016/j.jbc.2025.111026 · 被引用次数：1 · 研究领域：Endoplasmic Reticulum Stress and Disease、Genetics, Aging, and Longevity in Model Organisms、Cellular transport and secretion

The ER UPR plays a crucial role in maintaining proteostasis, with its dysfunction closely associated with aging and various diseases. However, how cells cope with ER UPR dysfunction remains largely unexplored. Here, we report that both ER-autonomous and ER-nonautonomous adaptive responses are activated by defects in the IRE-1/XBP-1 UPR branch in Caenorhabditis elegans. IRE-1/XBP-1 dysfunction not only triggers the activation of the PEK-1 UPR branch but also induces a lysosome-dependent cytosolic proteostatic response. Mechanistically, IRE-1/XBP-1 dysfunction downregulates phosphatidylcholine (PC) metabolism, reducing levels of membrane lipid PC. This PC deficiency drives BORC complex recruitment to lysosomes, triggering lysosomal activation. Furthermore, suppression of phosphatidylcholine metabolism alone sufficiently activates both the ER UPR and lysosomal pathways, thereby enhancing resilience to proteostatic stress and contributing to longevity. These findings provide insights into how cells integrate distinct adaptive responses to maintain systemic proteostasis when the ER UPR is compromised and identify phosphatidylcholine as a potent regulator of proteostasis and aging.