The α‐arrestin ARRDC3 regulates ubiquitin‐independent ALIX‐mediated GPCR lysosomal sorting (783.2)

Abstract

Endosomal sorting and lysosomal degradation of G‐protein coupled receptors (GPCRs) maintains cell homeostasis by attenuating receptor signaling and desensitizing cells to persistent activation. GPCR lysosomal sorting defects cause aberrant cellular responses that contribute to many diseases, including chronic inflammation and cancer metastasis. Here, we demonstrate that the human α‐arrestin ARRDC3 regulates the lysosomal degradation of protease‐activated receptor‐1 (PAR1), a GPCR for thrombin. PAR1 belongs to a subset of GPCRs, including the purinergic receptor P2Y1, that are sorted to lysosomes independent of receptor ubiquitination. Instead, PAR1 and P2Y1 are targeted to lysosomes by YPXnL motifs that are bound by the ESCRT adaptor protein ALIX. ARRDC3 is required for PAR1 degradation, but not for the degradation of ubiquitinated receptors. ARRDC3 regulates ALIX interaction with PAR1 and the ESCRT‐III protein CHMP4. Intriguingly, depletion of ARRDC3 or ALIX blocks recovery of thrombin‐induced dephosphorylation of Yap1, an effector of the Hippo cell proliferation pathway, suggesting that GPCR degradation is important for regulation of Hippo signaling. This study reveals a novel role for α‐arrestins in the ubiquitin‐independent, ALIX‐mediated endosomal trafficking of GPCRs, and demonstrates the importance of lysosomal sorting in the regulation of GPCR‐mediated proliferative signaling. Grant Funding Source: Supported by NIH NIGMS R01 GM090689