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

ABSTRACT: 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

SUBMITTER: Tong H 

PROVIDER: S-EPMC12796731 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature