The ubiquitin-proteasome system (UPS) and autophagy are two major pathways for maintaining cellular protein homeostasis. Increasing evidence has highlighted the complex interactions and crosstalk between these pathways; however, the specific molecules and mechanisms mediating the interplay between UPS and autophagy are still not fully elucidated. In this study, we discovered that knocking down the Drosophila cullin 2-RING ubiquitin ligase complex adaptor dZer1 impedes autophagy and autophagic flux. dZer1 interacts with the Drosophila p62/SQSTM1 homolog Ref(2)P, promoting its association with ubiquitinated proteins and degradation. Ref(2)P is a crucial player in regulating autophagy and the Keap1-Nrf2 pathway-mediated antioxidant response. Knockdown of dZer1 leads to the formation of Ref(2)P bodies, which sequester Keap1 and promote Nrf2/CncC-mediated antioxidant responses under oxidative stress conditions. These findings reveal the pivotal role of dZer1 in regulating autophagy and the Ref(2)P-Keap1-Nrf2-mediated oxidative stress response.