ER-to-Golgi transport machinery promotes the excessive cargo-triggered unfolded protein response

Abstract Disruptions to ER homeostasis trigger the unfolded protein response (UPR) to restore proteostatic balance. While defects in the secretory machinery are known to induce ER stress, it remains unclear whether specific trafficking components directly modulate UPR signaling. Here, we demonstrate that neuronal overexpression of the gap junction protein UNC-9 activates the IRE1-XBP1 arm of the UPR in C. elegans. Genetic deletion of ERGIC2 or ERGIC3—genes encoding COPII-associated proteins required for UNC-9 transport—suppresses this UPR activation, revealing an unexpected role for these factors beyond cargo trafficking. Mechanistically, ERGIC2 and ERGIC3 interact with the ER chaperone BiP, facilitating its release from IRE1 to enable UPR and alleviate cargo aggregation. Our findings redefine the UPR as a process dynamically regulated by early secretory components and provide novel insights into how cells integrate trafficking demand with stress adaptation, with implications for ER stress-associated diseases such as neurodegeneration.