Arrestin‐3 binds parkin and enhances parkin‐dependent mitophagy

Abstract

AbstractArrestins were discovered for their role in homologous desensitization of G‐protein‐coupled receptors (GPCRs). Later non‐visual arrestins were shown to regulate several signaling pathways. Some of these pathways require arrestin binding to GPCRs, the regulation of others is receptor independent. Here, we demonstrate that arrestin‐3 binds the E3 ubiquitin ligase parkin via multiple sites, preferentially interacting with its RING0 domain. Identification of the parkin domains involved suggests that arrestin‐3 likely relieves parkin autoinhibition and/or stabilizes the enzymatically active “open” conformation of parkin. Arrestin‐3 binding enhances ubiquitination by parkin of the mitochondrial protein mitofusin‐1 and facilitates parkin‐mediated mitophagy in HeLa cells. Furthermore, arrestin‐3 and its mutant with enhanced parkin binding rescue mitofusin‐1 ubiquitination and mitophagy in the presence of the Parkinson's disease‐associated R275W parkin mutant, which is defective in both functions. Thus, modulation of parkin activity via arrestin‐3 might be a novel strategy of anti‐parkinsonian therapy.