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

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

In: Nature Cell Biology, Jg. 13 (2011) ; Nr. 9, S. 1116–1123
ISSN: 1465-7392
Zeitschriftenaufsatz / Fach: Biologie
Fakultät für Biologie » Chemische Biologie
Abstract:
The AAA-ATPase VCP (also known as p97) cooperates with distinct
   cofactors to process ubiquitylated proteins in different cellular
   pathways(1-3). 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.