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PMID:22547407

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Citation

Dores, MR, Chen, B, Lin, H, Soh, UJ, Paing, MM, Montagne, WA, Meerloo, T and Trejo, J (2012) ALIX binds a YPX(3)L motif of the GPCR PAR1 and mediates ubiquitin-independent ESCRT-III/MVB sorting. J. Cell Biol. 197:407-19

Abstract

The sorting of signaling receptors to lysosomes is an essential regulatory process in mammalian cells. During degradation, receptors are modified with ubiquitin and sorted by endosomal sorting complex required for transport (ESCRT)-0, -I, -II, and -III complexes into intraluminal 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 (GPCR) for thrombin, is internalized after activation and sorted to lysosomes independent of ubiquitination and the ubiquitin-binding ESCRT components hepatocyte growth factor-regulated tyrosine kinase substrate and Tsg101. In this paper, we report that PAR1 sorted to ILVs of MVBs through an ESCRT-III-dependent pathway independent of ubiquitination. We further demonstrate that ALIX, a charged MVB protein 4-ESCRT-III interacting protein, bound to a YPX(3)L motif of PAR1 via its central V domain to mediate lysosomal degradation. This study reveals a novel MVB/lysosomal sorting pathway for signaling receptors that bypasses the requirement for ubiquitination and ubiquitin-binding ESCRTs and may be applicable to a subset of GPCRs containing YPX(n)L motifs.

Links

PubMed PMC3341166 Online version:10.1083/jcb.201110031

Keywords

Adenosine Triphosphatases/antagonists & inhibitors; Adenosine Triphosphatases/genetics; Adenosine Triphosphatases/metabolism; Amino Acid Motifs; Blotting, Western; Calcium-Binding Proteins/antagonists & inhibitors; Calcium-Binding Proteins/genetics; Calcium-Binding Proteins/metabolism; Cell Cycle Proteins/antagonists & inhibitors; Cell Cycle Proteins/genetics; Cell Cycle Proteins/metabolism; Endosomal Sorting Complexes Required for Transport/antagonists & inhibitors; Endosomal Sorting Complexes Required for Transport/genetics; Endosomal Sorting Complexes Required for Transport/metabolism; Endosomes/metabolism; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; HeLa Cells; Humans; Immunoprecipitation; Lysosomes/metabolism; Multivesicular Bodies/metabolism; Protein Binding; Protein Transport; RNA, Messenger/genetics; RNA, Small Interfering/genetics; Real-Time Polymerase Chain Reaction; Receptor, PAR-1/genetics; Receptor, PAR-1/metabolism; Ubiquitin/metabolism; Ubiquitination; Vacuolar Proton-Translocating ATPases/antagonists & inhibitors; Vacuolar Proton-Translocating ATPases/genetics; Vacuolar Proton-Translocating ATPases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:VPS4B

involved_in

GO:0090611: ubiquitin-independent protein catabolic process via the multivesicular body sorting pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P25116)

Seeded From UniProt

complete

HUMAN:VPS4B

involved_in

GO:0043162: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P55085)

Seeded From UniProt

complete

HUMAN:PAR1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8WUM4

F

Seeded From UniProt

complete

HUMAN:PAR1

located_in

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PAR1

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PAR2

located_in

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PAR2

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PDC6I

enables

GO:0031871: proteinase activated receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P25116

F

Seeded From UniProt

complete

HUMAN:PDC6I

involved_in

GO:0090611: ubiquitin-independent protein catabolic process via the multivesicular body sorting pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P25116)

Seeded From UniProt

complete

HUMAN:CHM4C

involved_in

GO:0090611: ubiquitin-independent protein catabolic process via the multivesicular body sorting pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P25116)

Seeded From UniProt

complete

HUMAN:CHM4B

involved_in

GO:0090611: ubiquitin-independent protein catabolic process via the multivesicular body sorting pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P25116)

Seeded From UniProt

complete

HUMAN:VPS4A

involved_in

GO:0090611: ubiquitin-independent protein catabolic process via the multivesicular body sorting pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P25116)

Seeded From UniProt

complete

HUMAN:VPS4A

involved_in

GO:0043162: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P55085)

Seeded From UniProt

complete

HUMAN:PAR1

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PAR1

part_of

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PAR2

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PAR2

part_of

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

Notes

See also

References

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