CRY1-CBS binding regulates circadian clock function and metabolism.

The FEBS journal 2021 Jan

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Circadian disruption influences metabolic health. Metabolism modulates circadian function. However, the mechanisms coupling circadian rhythms and metabolism remain poorly understood. Here, we report that cystathionine β-synthase (CBS), a central enzyme in one-carbon metabolism, functionally interacts with the core circadian protein cryptochrome 1 (CRY1). In cells, CBS augments CRY1-mediated repression of the CLOCK/BMAL1 complex and shortens circadian period. Notably, we find that mutant CBS-I278T protein, the most common cause of homocystinuria, does not bind CRY1 or regulate its repressor activity. Transgenic CbsZn/Zn mice, while maintaining circadian locomotor activity period, exhibit reduced circadian power and increased expression of E-BOX outputs. CBS function is reciprocally influenced by CRY1 binding. CRY1 modulates enzymatic activity of the CBS. Liver extracts from Cry1-/- mice show reduced CBS activity that normalizes after the addition of exogenous wild-type (WT) CRY1. Metabolomic analysis of WT, CbsZn/Zn , Cry1-/- , and Cry2-/- samples highlights the metabolic importance of endogenous CRY1. We observed temporal variation in one-carbon and transsulfuration pathways attributable to CRY1-induced CBS activation. CBS-CRY1 binding provides a post-translational switch to modulate cellular circadian physiology and metabolic control. © 2020 Federation of European Biochemical Societies.

Citation

Sibel Cal-Kayitmazbatir, Eylem Kulkoyluoglu-Cotul, Jacqueline Growe, Christopher P Selby, Seth D Rhoades, Dania Malik, Hasimcan Oner, Hande Asimgil, Lauren J Francey, Aziz Sancar, Warren D Kruger, John B Hogenesch, Aalim Weljie, Ron C Anafi, Ibrahim Halil Kavakli. CRY1-CBS binding regulates circadian clock function and metabolism. The FEBS journal. 2021 Jan;288(2):614-639