Caveolin-3 Undergoes SUMOylation by the SUMO E3 Ligase PIASy SUMOYLATION AFFECTS G-PROTEIN-COUPLED RECEPTOR DESENSITIZATION

Caveolin (Cav) proteins in the plasma membrane have numerous binding partners, but the determinants of these interactions are poorly understood. We show here that Cav-3 has a small ubiquitin-like modifier (SUMO) consensus motif (psi KX(D/E, where psi is a hydrophobic residue)) near the scaffolding domain and that Cav-3 is SUMOylated in a manner that is enhanced by the SUMO E3 ligase PIASy (protein inhibitor of activated STAT-y). Site-directed mutagenesis revealed that the consensus site lysine is the preferred SUMOylation site but that mutation of all lysines is required to abolish SUMOylation. Co-expression of a SUMOylation-deficient mutant of Cav-3 with beta-adrenergic receptors (beta ARs) alters the expression level of beta(2)ARs but not beta(1)ARs following agonist stimulation, thus implicating Cav-3 SUMOylation in the mechanisms for beta(2)AR but not beta(1)AR desensitization. Expression of endothelial nitric-oxide synthase (NOS3) was not altered by the SUMOylation-deficient mutant. Thus, SUMOylation is a covalent modification of caveolins that influence the regulation of certain signaling partners.