CRY1‐CBS binding regulates circadian clock function and metabolism
Open Access
- 8 May 2020
- journal article
- research article
- Published by Wiley in The FEBS Journal
- Vol. 288 (2), 614-639
- https://doi.org/10.1111/febs.15360
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.Keywords
Funding Information
- Defense Advanced Research Projects Agency (DARPA D17AP00003)
- Istanbul Kalkinma Ajansi (ISTKA‐TR/14/EVK/0039)
- National Institute of Neurological Disorders and Stroke (1R01NS054794‐06)
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