title: Endolysosomal sorting of ubiquitylated caveolin-1 is regulated by VCP and UBXD1 and impaired by VCP disease mutations.
abstract: The AAA-ATPase VCP (also known as p97) cooperates with distinct cofactors to process ubiquitylated proteins in different cellular pathways. VCP missense mutations cause a systemic degenerative disease in humans, but the molecular pathogenesis is unclear. We used an unbiased mass spectrometry approach and identified a VCP complex with the UBXD1 cofactor, which binds to the plasma membrane protein caveolin-1 (CAV1) and whose formation is specifically disrupted by disease-associated mutations. We show that VCP-UBXD1 targets mono-ubiquitylated CAV1 in SDS-resistant high-molecular-weight complexes on endosomes, which are en route to degradation in endolysosomes. Expression of VCP mutant proteins, chemical inhibition of VCP, or siRNA-mediated depletion of UBXD1 leads to a block of CAV1 transport at the limiting membrane of enlarged endosomes in cultured cells. In patient muscle, muscle-specific caveolin-3 accumulates in sarcoplasmic pools and specifically delocalizes from the sarcolemma. These results extend the cellular functions of VCP to mediating sorting of ubiquitylated cargo in the endocytic pathway and indicate that impaired trafficking of caveolin may contribute to pathogenesis in individuals with VCP mutations.
authors.affiliation: Centre for Medical Biotechnology, University of Duisburg-Essen, 45117 Essen, Germany.
authors.forename: Danilo
authors.initials: D
authors.lastname: Ritz
authors.forename: Maja
authors.initials: M
authors.lastname: Vuk
authors.forename: Philipp
authors.initials: P
authors.lastname: Kirchner
authors.forename: Monika
authors.initials: M
authors.lastname: Bug
authors.forename: Sabina
authors.initials: S
authors.lastname: Schütz
authors.forename: Arnold
authors.initials: A
authors.lastname: Hayer
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bremer
authors.forename: Caleb
authors.initials: C
authors.lastname: Lusk
authors.forename: Robert H
authors.initials: RH
authors.lastname: Baloh
authors.forename: Houkeun
authors.initials: H
authors.lastname: Lee
authors.forename: Timo
authors.initials: T
authors.lastname: Glatter
authors.forename: Matthias
authors.initials: M
authors.lastname: Gstaiger
authors.forename: Ruedi
authors.initials: R
authors.lastname: Aebersold
authors.forename: Conrad C
authors.initials: CC
authors.lastname: Weihl
authors.forename: Hemmo
authors.initials: H
authors.lastname: Meyer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000071183:Autophagy-Related Proteins; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism / Q000648:ultrastructure; D057809:HEK293 Cells; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism / Q000648:ultrastructure; D013058:Mass Spectrometry; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D009135:Muscular Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D011485:Protein Binding; D034622:RNA Interference; D051381:Rats; D012508:Sarcolemma / Q000378:metabolism; D057149:Ubiquitinated Proteins / Q000235:genetics / Q000378:metabolism; D000074405:Valosin Containing Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D051242:Caveolin 1; D018797:Cell Cycle Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D008164:Luminescent Proteins; C533572:UBXN6 protein, human; D057149:Ubiquitinated Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614180:Vcp protein, rat