Clock-mediated STIM1 regulation obligatory for bioenergetics in Sjogren's syndrome mouse model

The intricate connection between Ca2+ signaling, metabolism, circadian clock, and cell physiology remains poorly understood. Here, we identified that Ca2+ signaling has a bidirectional relationship in regulating circadian rhythm and its associated cell physiology including fluid secretion. Expression of STIM and Orai genes that modulate Ca2+ signaling, was dependent on the circadian rhythm. Mechanistically our data show that CLOCK gene (specifically BMAL1)-binding with STIM1 promoter was critical for regulating STIM1 expression. Furthermore, circadian-mediated regulation of mitochondrial bioenergetics was also dependent on CLOCK-mediated regulation of STIM1. To further assess Ca2+-dependent circadian rhythms, we used diet perturbation, where a Ca2+-deficient diet specifically impacts the CLOCK gene's rhythm and modulation of fluid secretion, which was further reversed by Ca2+ supplementation. In addition, circadian rhythm-mediated regulation of CLOCK genes, fluid secretion, and STIM1 genes was also disrupted in a Sjogren's syndrome (pSS))-like mouse model. Interestingly, samples from human pSS patients also showed dysregulation of clock and STIM1 genes that could alter cell physiology leading to immune activation and/or development of pSS-like phenotype. These results provide the first comprehensive evidence of a reciprocal relationship between circadian rhythm, Ca2+ signaling, and metabolism, which is critical for cell physiology.