PerspectiveCell Biology

Life Without Caveolae

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Science  28 Sep 2001:
Vol. 293, Issue 5539, pp. 2404-2405
DOI: 10.1126/science.1065677

Discovered by electron microscopists in the 1950s, caveolae—small surface pits in the plasma membrane—remain one of the most abundant yet puzzling features of many mammalian cells. The principal components of caveolae are proteins called caveolins. If caveolin-1, the isoform found in nonmuscle cells, is produced by cells normally lacking caveolae, then caveolae are formed (1); if cells that normally produce caveolin-1 become deficient in this protein they lose their caveolae (2). On page 2449 of this issue, Drab et al. (3) provide a thorough characterization of mice deficient in caveolin-1 that apparently have no caveolae.

An electron microscopist scanning the surface of a fat cell (adipocyte) that is covered in caveolae could hardly imagine life without these structures. Yet we do not know exactly what they do or how their characteristic shape is related to their cellular tasks (see the figure). It has been proposed that caveolae are important in signal transduction, forming a platform on which different signaling components can congregate (4, 5). In some cases, signaling components in the caveolae may remain inactive, held in check by caveolins until their activation and release by the appropriate external stimulus. The number of caveolae and amount of caveolin decrease dramatically in immortalized (transformed) cultured cells, hinting that caveolae are important for inhibiting certain signaling pathways that regulate cellular proliferation (4). However, it is becoming increasingly apparent that surface microdomains termed “lipid rafts,” of which caveolae are a subtype, could account for local concentrations of molecules required for efficient signaling (6). In fact, few signaling proteins are exclusively localized to caveolae, although notable exceptions include several putative calcium regulatory proteins (7). Also, certain cells with very complex signaling pathways such as lymphocytes and some neurons manage fine without caveolae. Even if these cells have proteins that can take the place of caveolins, they do not seem to need caveolae per se for signaling. Besides signaling, caveolae have been linked to cholesterol regulation: Caveolin binds to cholesterol, its production is controlled by cholesterol, and cells with mutations in caveolin exhibit pertubations in their cholesterol-rich lipid-raft domains (2). Again, although definitive evidence is lacking, these studies suggest that caveolae and caveolins may be involved in the regulation of intracellular and surface cholesterol.

Caveolae and caveolins.

(Left) An electron micrograph of small (65 nm) flask-shaped pits called caveolae in the plasma membrane of a human fibroblast. (Right) Caveolae are formed from caveolins, oligomeric integral membrane proteins. Caveolins are thought to have both their carboxyl and amino termini facing the cytoplasm and have palmitoyl groups (red squiggles) attached to carboxyl-terminus amino acids.

Given the variety of possible tasks attributed to caveolae, the generation of knockout mice deficient in caveolin-1 has been eagerly awaited. Drab and colleagues (3) report that their knockout mice are fertile and at first sight healthy, but, as they had hoped, the mice do show a remarkable lack of caveolae, at least in the tissues that they examined. This confirms the importance of caveolin-1 in caveolae formation but also shows that if compensatory pathways do exist (and one presumes that they do), then they do not involve caveolae or similar structures. So why are caveolae required at all?

Drab et al. question whether caveolae are involved in transcellular transport across endothelial cells. They find that their knockout mice have normal concentrations of the protein albumin in the cerebrospinal fluid, an indication that transendothelial transport is unaffected. Does this indicate that other noncaveolar pathways compensate for caveolae when they are absent, or are caveolae of little importance in transendothelial transport? The authors do see extensive changes in the cardiovascular system of their knockout animals. Using isolated aortic preparations, they detect defects in vascular relaxation, contractility, and myogenic tone due to impaired nitric oxide and calcium signaling. Previous studies have implicated caveolae in various calcium-dependent processes, including the local release of pulses of calcium from internal stores (“calcium sparks”) in muscle cells (8) and the generation of calcium waves in endothelia (9). The effects on nitric oxide generation are also intriguing and strongly implicate caveolae in the regulation of nitric oxide synthases, either directly or through the control of calcium ions. Supporting these findings, a synthetic caveolin-derived peptide specifically inhibited acetylcholine-induced vasodilation and nitric oxide generation in endothelia (10). Although the Drab et al. mice generally appeared healthy, subsequent tests showed that they were physically weak and that their lungs displayed severe abnormalities, with increased cell numbers and a disorganized architecture. The causes of these abnormalities are hard to discern but are at least consistent with hyperproliferation due to loss of the normal control of cell proliferation (4). If this turns out to be the case, it is not yet clear why hyperproliferation abnormalities are found in the lungs but not in other tissues that are normally caveolae-rich.

So, life goes on without caveolae. The phenotype of the knockout mice appears to be relatively mild in view of the loss of such an abundant structure, but the Drab et al. work is only the beginning of a more extensive investigation seeking subtle defects in these animals. With the linking of caveolins and caveolae to tumor suppression, chemotherapeutic drug resistance, and cholesterol regulation, it will be interesting to examine the response of caveolin-1-deficient mice to specific challenges. Perhaps most intriguingly, we still do not understand the importance of the characteristic shape of caveolae. The caveolae-deficient mice provide researchers with a tremendous new resource and surely have many more secrets to divulge.


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