PMID- 22547407
OWN - NLM
STAT- MEDLINE
DCOM- 20120621
LR  - 20211021
IS  - 1540-8140 (Electronic)
IS  - 0021-9525 (Print)
IS  - 0021-9525 (Linking)
VI  - 197
IP  - 3
DP  - 2012 Apr 30
TI  - ALIX binds a YPX(3)L motif of the GPCR PAR1 and mediates ubiquitin-independent 
      ESCRT-III/MVB sorting.
PG  - 407-19
LID - 10.1083/jcb.201110031 [doi]
AB  - 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.
FAU - Dores, Michael R
AU  - Dores MR
AD  - Department of Pharmacology, School of Medicine, University of California San 
      Diego, La Jolla, CA 92093, USA.
FAU - Chen, Buxin
AU  - Chen B
FAU - Lin, Huilan
AU  - Lin H
FAU - Soh, Unice J K
AU  - Soh UJ
FAU - Paing, May M
AU  - Paing MM
FAU - Montagne, William A
AU  - Montagne WA
FAU - Meerloo, Timo
AU  - Meerloo T
FAU - Trejo, JoAnn
AU  - Trejo J
LA  - eng
GR  - K12 GM068524/GM/NIGMS NIH HHS/United States
GR  - R01 GM090689/GM/NIGMS NIH HHS/United States
GR  - T32 HL007444/HL/NHLBI NIH HHS/United States
GR  - GM090689/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Cell Biol
JT  - The Journal of cell biology
JID - 0375356
RN  - 0 (CHMP4A protein, human)
RN  - 0 (CHMP4B protein, human)
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Endosomal Sorting Complexes Required for Transport)
RN  - 0 (PDCD6IP protein, human)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptor, PAR-1)
RN  - 0 (Ubiquitin)
RN  - EC 3.6.1.- (Adenosine Triphosphatases)
RN  - EC 3.6.1.- (Vacuolar Proton-Translocating ATPases)
RN  - EC 3.6.4.- (ATPases Associated with Diverse Cellular Activities)
RN  - EC 3.6.4.6 (VPS4A protein, human)
RN  - EC 3.6.4.6 (VPS4B protein, human)
SB  - IM
MH  - ATPases Associated with Diverse Cellular Activities
MH  - Adenosine Triphosphatases/antagonists & inhibitors/genetics/metabolism
MH  - Amino Acid Motifs
MH  - Blotting, Western
MH  - Calcium-Binding Proteins/antagonists & inhibitors/genetics/*metabolism
MH  - Cell Cycle Proteins/antagonists & inhibitors/genetics/*metabolism
MH  - Endosomal Sorting Complexes Required for Transport/antagonists & 
      inhibitors/genetics/*metabolism
MH  - Endosomes/metabolism
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Fluorescent Antibody Technique
MH  - HeLa Cells
MH  - Humans
MH  - Immunoprecipitation
MH  - Lysosomes/metabolism
MH  - Multivesicular Bodies/*metabolism
MH  - Protein Binding
MH  - Protein Transport
MH  - RNA, Messenger/genetics
MH  - RNA, Small Interfering/genetics
MH  - Real-Time Polymerase Chain Reaction
MH  - Receptor, PAR-1/genetics/*metabolism
MH  - Ubiquitin/*metabolism
MH  - Ubiquitination
MH  - Vacuolar Proton-Translocating ATPases/antagonists & 
      inhibitors/genetics/metabolism
PMC - PMC3341166
EDAT- 2012/05/02 06:00
MHDA- 2012/06/22 06:00
PMCR- 2012/10/30
CRDT- 2012/05/02 06:00
PHST- 2012/05/02 06:00 [entrez]
PHST- 2012/05/02 06:00 [pubmed]
PHST- 2012/06/22 06:00 [medline]
PHST- 2012/10/30 00:00 [pmc-release]
AID - jcb.201110031 [pii]
AID - 201110031 [pii]
AID - 10.1083/jcb.201110031 [doi]
PST - ppublish
SO  - J Cell Biol. 2012 Apr 30;197(3):407-19. doi: 10.1083/jcb.201110031.