Identification, Sequence, and Expression of an Invertebrate Caveolin Gene Family from the Nematode Caenorhabditis elegans

Abstract

Caveolae are vesicular organelles that represent an appendage of the plasma membrane. Caveolin, a 21-24-kDa integral membrane protein, is a principal component of caveolae membranes in vivo. Caveolin has been proposed to function as a plasma membrane scaffolding protein to organize and concentrate signaling molecules within caveolae, including heterotrimeric G proteins (␣ and ␤␥ subunits). In this regard, caveolin interacts directly with G ␣ subunits and can functionally regulate their activity. To date, three cDNAs encoding four subtypes of caveolin have been described in vertebrates. However, evidence for the existence of caveolin proteins in less complex organisms has been lacking. Here, we report the identification, cDNA sequence and genomic organization of the first invertebrate caveolin gene, Cav ce (for caveolin from Caenorhabditis elegans). The Cav ce gene, located on chromosome IV, consists of two exons interrupted by a 125-nucleotide intron sequence. The region of Cav ce that is strictly homologous to mammalian caveolins is encoded by a single exon in Cav ce. This suggests that mammalian caveolins may have evolved from the second exon of Cav ce. Cav ce is roughly equally related to all three known mammalian caveolins and, thus, could represent a common ancestor. Remarkably, the invertebrate Cav ce protein behaves like mammalian caveolins: (i) Cav ce forms a high molecular mass oligomer, (ii) assumes a cytoplasmic membrane orientation, and (iii) interacts with G proteins. A 20-residue peptide encoding the predicted G protein binding region of Cav ce possesses "GDP dissociation inhibitor-like activity" with the same potency as described earlier for mammalian caveolin-1. Thus, caveolin appears to be structurally and functionally conserved from worms to man. In addition, we find that there are at least two caveolin-related genes expressed in C. elegans, defining an invertebrate caveolin gene family. These results establish the nematode C. elegans as an invertebrate model system to study caveolae and caveolin in vivo. Caveolae are vesicular organelles that represent a subdivision of the plasma membrane (1, 2). Although they are found in most cell types, caveolae are most numerous in adipocytes, endothelial cells, fibroblasts, and muscle cells (smooth, skeletal, and cardiac). In transmission electron micrographs they can be distinguished by their characteristic shape: ϳ50-100-nm vesicles located at or near the plasma membrane (3, 4). Functionally, caveolae have been implicated in a variety of signal transduction related events, including signaling from G protein-coupled receptors and growth factor receptors (5-7). Caveolin, a 21-24-kDa protein, is an integral membrane component of caveolae (8-12). Caveolin co-purifies with lipid modified signaling molecules, such as G proteins (␣ and ␤␥ subunits), Src-family tyrosine kinases, and H-Ras (see Refs. 6, 9, and 13-18 and references cited within). These molecules appear to be tightly associated as a discrete complex with caveolin as shown using a polyhistidine-tagg...

Expression of Caveolin-1 Induces Premature Cellular Senescence in Primary Cultures of Murine Fibroblasts

“…These caveolin homo-and hetero-oligomers directly interact with cholesterol and represent the functional assembly units of caveolae . In addition, the caveolin gene family is structurally and functionally conserved from worms (C. elegans) to man (Tang et al, 1997), supporting the idea that caveolins play an essential role.…”

“…These caveolin homo-and hetero-oligomers directly interact with cholesterol and represent the functional assembly units of caveolae . In addition, the caveolin gene family is structurally and functionally conserved from worms (C. elegans) to man (Tang et al, 1997), supporting the idea that caveolins play an essential role.Most cells cannot divide indefinitely due to a process termed cellular senescence. Cellular senescence appears to be a fundamental feature of somatic cells, with the exception of most tumor cells and certain stem cells.…”

Caveolin-2 Is Required for Apical Lipid Trafficking and Suppresses Basolateral Recycling Defects in the Intestine ofCaenorhabditis elegans

“…Caenorhabditis elegans has two caveolin genes; cav-1 and cav-2 (Tang et al, 1997). cav-1 has been implicated in meiotic progression in the germ line (Scheel et al, 1999) and in neurotransmission at the neuromuscular junction (Parker et al, 2007).…”

“…Mutations in caveolin-1 have also been shown to be associated with the rare lipodystrophies: Berardinelli-Seip congenital lipodystrophy (OMIM:269700) and an atypical partial lipodystrophy and hypertriglyceridemia (Cao et al, 2008;Kim et al, 2008a). Caveolin-1 is also required for liver regeneration (Fernandez et al, 2006;Frank and Lisanti, 2007).Caenorhabditis elegans has two caveolin genes; cav-1 and cav-2 (Tang et al, 1997). cav-1 has been implicated in meiotic progression in the germ line (Scheel et al, 1999) and in neurotransmission at the neuromuscular junction (Parker et al, 2007).…”

Limb-girdle Muscular Dystrophy (LGMD-1C) Mutants of Caveolin-3 Undergo Ubiquitination and Proteasomal Degradation

“…Twelve amino acid residues are absolutely conserved in all three human caveolins as well as the two Caenorhabditis elegans caveolins (40), and the LGMD-1C mutants map to 2 of these 12 invariant residues, Pro 104 and Phe 64 (39). In addition, alanine scanning mutagenesis of a peptide encoding the caveolin-scaffolding domain reveals that the FTV(T/S) sequence in caveolins 1 and 3 is important for recognition of caveolin binding, signaling proteins (41); the FT dipeptide of the FTVT/S sequence is deleted in one LGMD-1C family.…”