PEX14 acts as the interface linking optineurin to cell type-selective pexophagy

Abstract

AbstractPeroxisome degradation, known as pexophagy, is essential for eliminating surplus and dysfunctional peroxisomes, with dysregulation linked to various diseases. Previous research revealed that ectopic expression of optineurin (OPTN), a versatile autophagy adaptor involved in multiple autophagic pathways (e.g., mitophagy, aggrephagy, and xenophagy), triggers pexophagy in HEK-293 cells. However, the underlying mechanism remained elusive. Here, we demonstrate that OPTN-mediated pexophagy is a cell type-specific process. In addition, using proximity labeling, we identified PEX14, a peroxisomal membrane protein, as an OPTN-interacting partner. GFP-Trap analyses confirmed this interaction and revealed that PEX14 and OPTN interact through their respective coiled-coil and C-terminal ubiquitin-binding domains, independently of ubiquitin. Furthermore, our results indicate that the C-terminal half of OPTN-GFP induces pexophagy by oligomerization with endogenous OPTN. Overall, these findings propose PEX14 as a docking factor for OPTN at the peroxisomal membrane, facilitating the connection between peroxisomes and the autophagic membrane scaffold during OPTN-mediated pexophagy.