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Regulation of the E3 Ligase WWP2 by GPCR Activation and CDH1 Mediates ALIXdependent Lysosomal Sorting
Author(s) -
Shahid Shafaq,
Kotsis Christopher,
Singh Harjoyt,
Dores Michael Robert
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06705
Subject(s) - g protein coupled receptor , microbiology and biotechnology , endosome , ubiquitin ligase , endocytic cycle , ubiquitin , biology , tsg101 , escrt , signal transduction , signal transducing adaptor protein , receptor , endocytosis , intracellular , biochemistry , microvesicles , microrna , gene
G protein‐coupled receptors (GPCRs) comprise the largest and most diverse family of membrane receptors. Dysregulated GPCR signaling is linked to multiple diseases, including inflammation, vascular disease, and many cancers. Attenuation of GPCR signaling is mediated by internalization and lysosomal degradation. GPCRs signal to their endocytic sorting machinery to initiate trafficking at the plasma membrane as well as at the limiting membrane of early and late endosomes. GPCRs like protease‐activated receptor 1 (PAR1) can stimulate the ubiquitination and activation of ALIX, an adaptor protein that sorts GPCRs with intracellular YPX n L motifs into budding intraluminal vesicles at multivesicular endosomes. This process is mediated by the NEDD4‐family E3 ubiquitin ligase WWP2. Here, we show that stimulation of multiple YPX n L‐motif receptors, including PAR1, the purinergic receptor P 2 Y 1 and the histamine H 2 receptor, induce ubiquitination of WWP2 during receptor lysosomal sorting. In addition, we have identified a novel role for the E3 ligase CDH1 in modulating WWP2 ubiquitination. Transient depletion of CDH1 leads to elevated WWP2 ubiquitination and receptor downregulation, suggesting a potential mechanism for conditionally modulating WWP2 activity during receptor trafficking. Our current research aims to elucidate the common connection between the signaling pathways activated by YPX n L GPCRs and the regulation of CDH1 and WWP2.