Calcium and SOL Protease Mediate Temperature Resetting of Circadian Clocks

Graphical Abstract Highlights d Calcium and the protease SOL trigger TIM degradation in response to thermal input d Thermal TIM degradation resets the Drosophila circadian pacemaker d TIM integrates light and temperature input d In mammals, the SOL homolog also impacts circadian thermal responses In Brief Temperature phase shifts the Drosophila circadian clock through the regulated degradation of the pacemaker protein TIMELESS. SUMMARY Circadian clocks integrate light and temperature input to remain synchronized with the day/night cycle. Although light input to the clock is well studied, the molecular mechanisms by which circadian clocks respond to temperature remain poorly understood. We found that temperature phase shifts Drosophila circadian clocks through degradation of the pacemaker protein TIM. This degradation is mechanisti-cally distinct from photic CRY-dependent TIM degradation. Thermal TIM degradation is triggered by cytosolic calcium increase and CALMODULIN binding to TIM and is mediated by the atypical calpain protease SOL. This thermal input pathway and CRY-dependent light input thus converge on TIM, providing a molecular mechanism for the integration of circadian light and temperature inputs. Mammals use body temperature cycles to keep peripheral clocks synchronized with their brain pacemaker. Interestingly, downregulating the mammalian SOL homolog SOLH blocks thermal mPER2 degradation and phase shifts. Thus, we propose that circadian thermosensation in insects and mammals share common principles.