Abstract

Caveolae are plasma membrane microdomains that localise receptors and signalling intermediates within an environment where they can efficiently trigger downstream events. While present in most cells types, they are particularly abundant in vascular smooth muscle cells and endothelial cells (ECs), where they regulate low density lipoprotein trans-cytosis, NO production and inflammation. Cavin-1 is a protein required for caveolae maturation, such that its deletion results in no detectable caveolae and the down-regulation of “caveolin” scaffolding proteins. However, the cellular processes regulating cavin-1 function are poorly understood. Proteomic screening and biochemical experiments have identified cavin-1 as a novel interacting protein of the cytokine-inducible E3 ubiquitin ligase component “suppressor of cytokine signalling-3” (SOCS3), a key inhibitor of IL-6-mediated pro-inflammatory signalling in ECs. We hypothesise d that the SOCS3/cavin-1 interaction may be important in controlling caveola stability and/or IL-6 signalling. In support of this hypothesis, cavin-1 protein levels were significantly reduced in SOCS3−/− murine embryonic fibroblasts (MEFs) compared with WT MEFs in the absence of any changes in cavin-1 mRNA. This was associated with a reduced stability of the cavin-1 protein in SOCS3−/− MEFs (t1/2=2 hr) versus WT MEFs (t1/2>7 hr), significantly reduced levels of caveolin-1 and a parallel decrease in the number of caveolae detectable  in SOCS3−/− MEFs by transmission electron microscopy. Confocal imaging experiments also revealed that cavin-1 was required for SOCS3 localisation to the plasma membrane and effective SOCS3-mediated inhibition of IL-6 signalling. Together, these data demonstrate an important interaction between cavin-1 and SOCS3 responsible for reciprocal regulation of their respective functions.