Caveolae: One Function or Many?

Caveolae are small, bulb-shaped plasma membrane invaginations. Mutations that ablate caveolae lead to diverse phenotypes in mice and humans, making it challenging to uncover their molecular mechanisms. Caveolae have been described to function in endocytosis and transcytosis (a specialized form of endocytosis) and in maintaining membrane lipid composition, as well as acting as signaling platforms. New data also support a model in which the central function of caveolae could be related to the protection of cells from mechanical stress within the plasma membrane. We present evidence for these diverse roles and consider in vitro and in vivo experiments confirming a mechanoprotective role. We conclude by highlighting current gaps in our knowledge of how mechanical signals may be transduced by caveolae.

Caveolae protect endothelial cells from membrane rupture during increased cardiac output.

Caveolae are strikingly abundant in endothelial cells, yet the physiological functions of caveolae in endothelium and other tissues remain incompletely understood. Previous studies suggest a mechanoprotective role, but whether this is relevant under the mechanical forces experienced by endothelial cells in vivo is unclear. In this study we have sought to determine whether endothelial caveolae disassemble under increased hemodynamic forces, and whether caveolae help prevent acute rupture of the plasma membrane under these conditions. Experiments in cultured cells established biochemical assays for disassembly of caveolar protein complexes, and assays for acute loss of plasma membrane integrity. In vivo, we demonstrate that caveolae in endothelial cells of the lung and cardiac muscle disassemble in response to acute increases in cardiac output. Electron microscopy and two-photon imaging reveal that the plasma membrane of microvascular endothelial cells in caveolin 1(-/-) mice is much more susceptible to acute rupture when cardiac output is increased. These data imply that mechanoprotection through disassembly of caveolae is important for endothelial function in vivo.

Organelle dynamics and membrane trafficking in apoptosis and autophagy.

The accurate control of cell death is a vital aspect of development in metazoans and plays crucial roles in the prevention of disease. Apoptosis is the main form of regulated cell death in multicellular organisms, although there are other contributory pathways. During apoptosis, mammalian cells undergo dramatic changes in organelle structure ad organisation that define the apoptotic execution phase. Although the roles of apoptotic protease machinery (the caspases) in these rearrangements are quite well understood, the purpose of organelle disruption during cell death is not yet entirely appreciated. Indeed, recent evidence implicates caspase targeting of organellar proteins and subsequent organelle disruption upstream of apoptotic execution proper, suggesting the existence of pathways linking organelle damage to cell death. In this review, we describe the changes to the endomembrane system that are inherent during the apoptotic execution phase, and examine the evidence for endomembrane-mediated pathways towards apoptotic execution. We also discuss aspects of the molecular control of autophagy - an important contributor to a cell's response to stress, and a membrane trafficking process whose regulation is linked to the apoptotic machinery at multiple levels.