Limb-girdle muscular dystrophy (LGMD-1C) mutants of caveolin-3 undergo ubiquitination and proteasomal degradation - Treatment with proteasomal inhibitors blocks the dominant negative effect of LGMD-1C mutants and rescues wild-type caveolin-3

Caveolin-3 is the principal structural protein of caveolae in striated musc le. Autosomal dominant limb-girdle muscular dystrophy (LGMD-1C) in humans i s due to mutations (Delta TFT and Pro --> Leu) within the CAV3 gene. We hav e shown that LGMD-1C mutations lead to formation of unstable aggregates of caveolin-3 that are retained intracellularly and are rapidly degraded. The mechanism by which LGMD-1C mutants of caveolin-3 are degraded remains unkno wn. Here, we show that LGMD-1C mutants of caveolin-3 undergo ubiquitination -proteasomal degradation. Treatment with proteasomal inhibitors (MG-132, MG -115, lactacystin, or proteasome inhibitor I), but not lysosomal inhibitors , prevented degradation of LGMD-1C caveolin-3 mutants. In the presence of M G-132, LGMD-1C caveolin-3 mutants accumulated within the endoplasmic reticu lum and did not reach the plasma membrane. LGMD-1C mutants of caveolin-3 be have in a dominant negative fashion, causing intracellular retention and de gradation of wild-type caveolin-3, Interestingly, in cells co-expressing wi ldtype and mutant forms of caveolin-3, MG-132 treatment rescued wild-type c aveolin-3; wild-type caveolin-3 was not degraded and reached the plasma mem brane. These results may have clinical implications for treatment of patien ts with LGMD-1C.