CRY1-CBS binding regulates circadian clock function and metabolism.

May 9, 2020The FEBS journal

How CRY1 and CBS interaction controls the body’s daily clock and metabolism

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Abstract

Cystathionine β-synthase (CBS) functionally interacts with the core circadian protein cryptochrome 1 (CRY1) and influences circadian rhythms.

CBS enhances the repressive activity of CRY1 on the CLOCK/BMAL1 complex, leading to a shortened circadian period.
The mutant CBS-I278T, linked to homocystinuria, fails to bind CRY1 or regulate its repressor activity.
Transgenic mice with altered CBS show unchanged circadian locomotor activity but reduced circadian power and heightened expression of E-BOX outputs.
CRY1 binding reciprocally regulates CBS enzymatic activity, with liver extracts from Cry1 mice displaying reduced CBS function that normalizes with wild-type CRY1 addition.
Metabolomic analysis reveals temporal variations in one-carbon and transsulfuration pathways linked to CRY1's activation of CBS.

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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 Cbs 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 Cry1mice show reduced CBS activity that normalizes after the addition of exogenous wild-type (WT) CRY1. Metabolomic analysis of WT, Cbs, Cry1, and Cry2samples 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. Zn/Zn -/-Zn/Zn -/--/-

CRY1-CBS binding regulates circadian clock function and metabolism.

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