CRY1‐CBS binding regulates circadian clock function and metabolism

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 b-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 Zn/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 À/À mice show reduced CBS activity that normalizes after the addition of exogenous wildtype (WT) CRY1. Metabolomic analysis of WT, Cbs Zn/Zn , Cry1 À/À , and Cry2 À/À 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.

The Arg-293 of Cryptochrome1 is responsible for the allosteric regulation of CLOCK-CRY1 binding in circadian rhythm

“…Third, when compared with CRY2, CRY1 is a more potent repressor of BMAL1/CLOCK-transactivation on E-boxes (22,23). Finally, CRY1 specifically interacts with Cystathionine β-synthase by regulating one-carbon and transsulfuration pathways (24). All these studies show functional differences between the CRYs in the circadian clock mechanism.…”

Deficiency of circadian gene cryptochromes in bone marrow‐derived cells protects against atherosclerosis in LDLR −/− mice

“…43 Moreover, although the functions of Cry1 and Cry2 in the core circadian clock were initially thought to be redundant, they have distinct and separable roles in the circadian molecular clock 44 and peripheral metabolism rhythms. 45 For experimental and drug design, it would be important in the future to modulate both Cry1 and Cry2 simultaneously.…”

Coupled network of the circadian clocks: a driving force of rhythmic physiology

“…In CRY1-KO mice, reduced cystathionine b-synthase (CBS) activity levels were reported that were rescued by adding exogenous CRY1. CRY1-induced CBS activation led to post-translational switch that modulated metabolism [276]. Interestingly, the circadian regulator Nocturnin, a rhythmic gene encoding a deadenylase thought to be involved in the removal of poly(A) tails, controls glucose and lipid metabolism [277], as well as metabolic adaptation in brown adipose tissue [278].…”