Loss of DDI2 rewires proteostasis through CCN1-driven compensatory autophagy.

The ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP) are the primary mechanisms for protein degradation, yet the molecular mechanisms linking them remain unclear. We show that loss of the UPS shuttle-protease DDI2 in diverse human and murine cells leads to a proteotoxic stress response driven by the intracellular accumulation of the secretory protein CCN1. Misfolded CCN1 is normally extracted from the endoplasmic reticulum by a DDI2-p97 complex and directed to lysosomes for degradation. In the absence of DDI2, CCN1 builds up, produces reactive oxygen species, and triggers compensatory autophagy; CCN1 knockout or ROS scavenging attenuates this response. Loss of DDI2 also impairs CCN1-LAMP1 colocalization, suggesting that DDI2 functions as a selective cargo receptor linking the UPS and ALP. These findings reveal a stress-responsive DDI2-CCN1 axis that reshapes proteostasis and highlight DDI2 as a potential therapeutic vulnerability in proteasome-dependent cancers.