Journal Article

Endolysosomal sorting of ubiquitylated caveolin-1 is regulated by VCP and UBXD1 and impaired by VCP disease mutations

Glatter, Timo, Schütz, Sabina, Bug, Monika, Kirchner, Philipp, Lee, Houkeun, Baloh, Robert H., Meyer, Hemmo, Lusk, Caleb, Aebersold, Ruedi, Ritz, Danilo, Bremer, Sebastian, Weihl, Conrad C., Vuk, Maja, Gstaiger, Matthias, Hayer, Arnold

2011

Overview

VCP (also called p97) recognizes and interacts with ubiquitylated cargo molecules that are destined for proteasomal degradation. Meyer and colleagues show that VCP, together with its cofactor UBXD1, sorts ubiquitylated caveolin-1 to the endolysosome system. Mutations in VCP that are associated with human degenerative diseases lack this ability. The AAA-ATPase VCP (also known as p97) cooperates with distinct cofactors to process ubiquitylated proteins in different cellular pathways 1 , 2 , 3 . VCP missense mutations cause a systemic degenerative disease in humans, but the molecular pathogenesis is unclear 4 , 5 . 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 6 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/2489/144 / 631/208/737 / 631/80/313 / 692/420 / Adaptor Proteins, Signal Transducing / Adaptor Proteins, Vesicular Transport / Adenosine Triphosphatases - genetics / Adenosine Triphosphatases - metabolism / Animals / Autophagy-Related Proteins / Biomedical and Life Sciences / Blotting, Western / Cancer Research / Carrier Proteins - genetics / Carrier Proteins - metabolism / Caveolin 1 - genetics / Caveolin 1 - metabolism / Cell Biology / Cell cycle / Cell Cycle Proteins - genetics / Cell Cycle Proteins - metabolism / Cell Line, Tumor / Cells, Cultured / Degeneration (Pathology) / Developmental Biology / Diagnosis / Disease / Endoplasmic reticulum / Endosomal Sorting Complexes Required for Transport - genetics / Endosomal Sorting Complexes Required for Transport - metabolism / Endosomes - metabolism / Endosomes - ultrastructure / Gene mutations / Genetic aspects / Health aspects / HEK293 Cells / Humans / letter / Life Sciences / Luminescent Proteins - genetics / Luminescent Proteins - metabolism / Lysosomes - metabolism / Lysosomes - ultrastructure / Mass Spectrometry / Membranes / Microscopy, Electron / Microscopy, Fluorescence / Muscular Diseases - genetics / Muscular Diseases - metabolism / Muscular Diseases - pathology / Mutation / Pathogenesis / Protein Binding / Proteins / Rats / Risk factors / RNA Interference / Sarcolemma - metabolism / Scientific imaging / Stem Cells / Ubiquitinated Proteins - genetics / Ubiquitinated Proteins - metabolism / Valosin Containing Protein