Title: CRY1-CBS binding regulates circadian clock function and metabolism.
Authors: Cal-Kayitmazbatir, Sibel; Kulkoyluoglu-Cotul, Eylem; Growe, Jacqueline; Selby, Christopher P; Rhoades, Seth D; Malik, Dania; Oner, Hasimcan; Asimgil, Hande; Francey, Lauren J; Sancar, Aziz; Kruger, Warren D; Hogenesch, John B; Weljie, Aalim; Anafi, Ron C; Kavakli, Ibrahim Halil
Published In FEBS J, (2021 01)
Abstract: 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.
PubMed ID: 32383312
MeSH Terms: ARNTL Transcription Factors/genetics; ARNTL Transcription Factors/metabolism; Amino Acid Sequence; Animals; CLOCK Proteins/genetics; CLOCK Proteins/metabolism; Circadian Clocks/genetics*; Circadian Rhythm/genetics*; Cryptochromes/deficiency; Cryptochromes/genetics*; Cystathionine beta-Synthase/genetics*; Cystathionine beta-Synthase/metabolism; E-Box Elements; Female; HEK293 Cells; Humans; Male; Metabolic Networks and Pathways/genetics; Metabolome/genetics*; Mice; Mice, Knockout; Mutation; Period Circadian Proteins/genetics; Period Circadian Proteins/metabolism; Protein Binding; Protein Processing, Post-Translational*; Sequence Alignment; Sequence Homology, Amino Acid; Signal Transduction