A role for caveolar proteins in regulation of the circadian clock

Caveolae are specialized invaginations of the plasma membrane that are formed by the co-assembly of caveolin integral membrane proteins and a cytoplasmic cavin coat complex. Previous work has proposed an interaction of the cavin coat protein, CAVIN3, with the key circadian clock protein, PER2. Here we show that cavin proteins can play a role in the regulation of the circadian clock by external stimuli. Loss of Cavin1 in mice caused a shortening of the free-running period of locomotor activity. CAVIN1 and CAVIN3 were found to play a central role in core clock dynamics with either cavin protein directly interacting with PER2 and their perturbation leading to significant disruption in core clock mRNA expression and CRY1 protein oscillation. In cells, association of cavins and PER2 was increased upon caveola disassembly caused by oxidative stress or by calcium influx, stimuli linked to circadian clock regulation. We thus propose that the caveola system can play a modulatory role in circadian regulation through the cavin proteins.