201. A phosphoinositide-binding cluster in cavin1 acts as a molecular sensor for cavin1 degradation
- Author
-
Oleksiy Kovtun, Brett M. Collins, Kerrie-Ann McMahon, Vikas A. Tillu, and Robert G. Parton
- Subjects
Cytoplasm ,Proteasome Endopeptidase Complex ,Caveolin 1 ,Biology ,Caveolae ,Phosphatidylinositols ,Madin Darby Canine Kidney Cells ,03 medical and health sciences ,Dogs ,0302 clinical medicine ,Animals ,Humans ,Molecular Biology ,Integral membrane protein ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,Binding Sites ,Ubiquitination ,Membrane Proteins ,RNA-Binding Proteins ,Cell Biology ,Protein Structure, Tertiary ,Cell biology ,Cytosol ,Membrane protein ,MCF-7 Cells ,Brief Reports ,Signal transduction ,030217 neurology & neurosurgery ,Signal Transduction ,Cavin - Abstract
Cavin1 degradation is primarily mediated by the ubiquitin proteasome system. The phosphoinositide-binding region in cavin1 acts as a molecular switch for cavin1 degradation upon release of cavins in cytosol. This mechanism may help to maintain low levels of free cytosolic cavins at steady state., Caveolae are abundant surface organelles implicated in a range of cellular processes. Two classes of proteins work together to generate caveolae: integral membrane proteins termed caveolins and cytoplasmic coat proteins called cavins. Caveolae respond to membrane stress by releasing cavins into the cytosol. A crucial aspect of this model is tight regulation of cytosolic pools of cavin under resting conditions. We now show that a recently identified region of cavin1 that can bind phosphoinositide (PI) lipids is also a major site of ubiquitylation. Ubiquitylation of lysines within this site leads to rapid proteasomal degradation. In cells that lack caveolins and caveolae, cavin1 is cytosolic and rapidly degraded as compared with cells in which cavin1 is associated with caveolae. Membrane stretching causes caveolar disassembly, release of cavin complexes into the cytosol, and increased proteasomal degradation of wild-type cavin1 but not mutant cavin1 lacking the major ubiquitylation site. Release of cavin1 from caveolae thus leads to exposure of key lysine residues in the PI-binding region, acting as a trigger for cavin1 ubiquitylation and down-regulation. This mutually exclusive PI-binding/ubiquitylation mechanism may help maintain low levels of cytosolic cavin1 in resting cells, a prerequisite for cavins acting as signaling modules following release from caveolae.
- Published
- 2015