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Significance One-third of the mammalian proteome is transported by the cytoplasmic coat protein complex-II (COPII) secretory vesicles. However, how this core coat machinery is regulated to meet the metabolic demand in response to alterations of the nutritional state remains largely unexplored. Here, we show that COPII vesicle trafficking is highly dynamic and responsive to nutrient availability fluctuations. We also uncover that the nutrient-sensing inositol-requiring enzyme 1α (IRE1α)–transcription factor X-box binding protein 1 (XBP1s) axis links COPII-mediated trafficking to nutrient availability. Furthermore, restoration of XBP1s in mice lacking hepatic IRE1α activates COPII-dependent lipoprotein traffic and reverses hepatosteatosis and hypolipidemia. Hence, we reveal a mechanism for the orchestration of COPII vesicle trafficking in response to nutrient availability.

Coupling of COPII vesicle trafficking to nutrient availability by the IRE1α-XBP1s axis