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ALIX interacts with a YPX3L motif of Protease‐Activated Receptor 1 and mediates MVB/Lysosomal sorting through an ESCRT‐III‐dependent pathway independent of ubiquitination
Author(s) -
Dores Michael Robert,
Chen Buxin,
Lin Huilan,
Soh Unice J.K.,
Paing May M,
Montagne William A,
Meerloo Timo,
Trejo JoAnn
Publication year - 2012
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.26.1_supplement.780.2
Subject(s) - escrt , ubiquitin , tsg101 , microbiology and biotechnology , endosome , receptor , signal transducing adaptor protein , ubiquitin ligase , chemistry , protein targeting , deubiquitinating enzyme , signal transduction , biology , intracellular , biochemistry , membrane protein , microvesicles , gene , microrna , membrane
The sorting of signaling receptors to lysosomes is an essential regulatory process. During degradation, receptors are modified with ubiquitin and sorted by ESCRT‐0, ‐I, ‐II and ‐III complexes into intralumenal vesicles (ILVs) of multivesicular bodies (MVBs). However, it remains unclear whether a single universal mechanism mediates MVB sorting of all receptors. We previously showed that protease‐activated receptor‐1 (PAR1), a G protein‐coupled receptor for thrombin, is internalized after activation and sorted to lysosomes independent of ubiquitination and the ubiquitin‐binding ESCRTs, Hrs and Tsg101. Here, we now report that PAR1 sorts to ILVs of MVBs through an ESCRT‐III‐dependent pathway independent of ubiquitination. We further demonstrate that ALIX, a CHMP4/ESCRT‐III interacting protein, mediates PAR1/ESCRT‐III interaction. ALIX binds directly to a YPX n L motif localized within the PAR1 second intracellular loop via its central V‐domain and directs the lysosomal degradation of PAR1. This study reveals a novel MVB/lysosomal sorting pathway for signaling receptors that bypasses the requirement for ubiquitination and ubiquitin‐binding ESCRTs. Supported by NIH R01GM090689and University of California Tobacco Related Disease Research Program 19FT0157