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CRY1‐CBS binding regulates circadian clock function and metabolism
Author(s) -
CalKayitmazbatir Sibel,
KulkoyluogluCotul 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
Publication year - 2021
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.15360
Subject(s) - circadian rhythm , cryptochrome , circadian clock , transsulfuration , cystathionine beta synthase , biology , endogeny , metabolism , repressor , period (music) , microbiology and biotechnology , endocrinology , medicine , biochemistry , enzyme , cysteine , gene expression , gene , physics , acoustics
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 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 −/− mice show reduced CBS activity that normalizes after the addition of exogenous wild‐type (WT) CRY1. Metabolomic analysis of WT, Cbs Zn/Zn , Cry 1 −/− , 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.