CRY1-CBS binding regulates circadian clock function and metabolism

Abstract

<jats:title>Abstract</jats:title><jats:p>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 Cryptochrome1 (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 <jats:italic>Cbs</jats:italic><jats:sup>Zn/Zn</jats:sup> 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 <jats:italic>Cry</jats:italic>1<jats:sup>−/−</jats:sup> mice show reduced CBS activity that normalizes after the addition of exogenous wild type (WT) CRY1. Metabolomic analysis of WT, <jats:italic>Cbs</jats:italic><jats:sup>Zn/Zn</jats:sup>, <jats:italic>Cry</jats:italic>1<jats:sup>−/−</jats:sup>, and <jats:italic>Cry2</jats:italic><jats:sup>−/−</jats:sup> 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.</jats:p>

Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation

“…As expected, CBS mRNA levels were lower in Cbs −/− stomachs (FD = 0.08–0.14 compared to Cbs +/+ stomachs, Additional file 22 ). Despite low sample numbers, pathway analysis using PANTHER (FDR < 0.05) identified “circadian regulation of gene expression” as the top upregulated pathway, consistent with a recent study reporting a distinct role for CBS in circadian function [ 38 ]. More pertinent to this study, several immune-related processes were also significantly upregulated including “complement activation” and “defense response to bacterium,” indicative of an inflammatory state in CBS -deficient stomachs (Additional file 23 ) and concurring with our earlier observations.…”

Proteome analysis of the circadian clock protein PERIOD2

“…Circadian clock might regulate the other pathways through interactions with the critical proteins/enzymes. For example, CRY1 has posttranslational functions out of the context of the core clock mechanism and binds to G‐proteins and cysteine beta‐synthase and regulates their activity and, in turn, regulates cellular metabolism 17,72 . In a similar way, the circadian clock might regulate HK1 activity by PER2‐HK1 interaction to regulate glycolysis, which is needed to be shown experimentally.…”

“…Moreover, post‐translational stability and modifications are actively regulated by the circadian clock. In fact, a recent study highlighted that CRY1‐induced cystathionine β‐synthase activity modulates amino acid metabolism 17 . On the other hand, another study shows that 50% of detected metabolites are controlled by the circadian clock 18 …”

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

“…In CRY1‐KO mice, reduced cystathionine β‐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].…”