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AP-3 regulates PAR1 ubiquitin-independent MVB/lysosomal sorting via an ALIX-mediated pathway. Mol Biol Cell 2012 Sep;23(18):3612-23

Date

07/27/2012

Pubmed ID

22833563

Pubmed Central ID

PMC3442409

DOI

10.1091/mbc.E12-03-0251

Scopus ID

2-s2.0-84866355290   40 Citations

Abstract

The sorting of signaling receptors within the endocytic system is important for appropriate cellular responses. After activation, receptors are trafficked to early endosomes and either recycled or sorted to lysosomes and degraded. Most receptors trafficked to lysosomes are modified with ubiquitin and recruited into an endosomal subdomain enriched in hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), a ubiquitin-binding component of the endosomal-sorting complex required for transport (ESCRT) machinery, and then sorted into intraluminal vesicles (ILVs) of multivesicular bodies (MVBs)/lysosomes. However, not all receptors use ubiquitin or the canonical ESCRT machinery to sort to MVBs/lysosomes. This is exemplified by protease-activated receptor-1 (PAR1), a G protein-coupled receptor for thrombin, which sorts to lysosomes independent of ubiquitination and HRS. We recently showed that the adaptor protein ALIX binds to PAR1, recruits ESCRT-III, and mediates receptor sorting to ILVs of MVBs. However, the mechanism that initiates PAR1 sorting at the early endosome is not known. We now report that the adaptor protein complex-3 (AP-3) regulates PAR1 ubiquitin-independent sorting to MVBs through an ALIX-dependent pathway. AP-3 binds to a PAR1 cytoplasmic tail-localized tyrosine-based motif and mediates PAR1 lysosomal degradation independent of ubiquitination. Moreover, AP-3 facilitates PAR1 interaction with ALIX, suggesting that AP-3 functions before PAR1 engagement of ALIX and MVB/lysosomal sorting.

Author List

Dores MR, Paing MM, Lin H, Montagne WA, Marchese A, Trejo J

Author

Adriano Marchese PhD Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adaptor Protein Complex 3
Adaptor Protein Complex delta Subunits
Calcium-Binding Proteins
Cell Cycle Proteins
Endosomal Sorting Complexes Required for Transport
HeLa Cells
Humans
Immunoblotting
Lysosomes
Microscopy, Confocal
Models, Biological
Multivesicular Bodies
Protein Binding
Protein Transport
RNA Interference
Receptor, PAR-1
Signal Transduction
Ubiquitin
Ubiquitination