CRY1-CBS binding regulates circadian clock function and metabolism

被引:26
作者
Cal-Kayitmazbatir, Sibel [1 ]
Kulkoyluoglu-Cotul, Eylem [2 ]
Growe, Jacqueline [3 ]
Selby, Christopher P. [4 ]
Rhoades, Seth D. [3 ]
Malik, Dania [3 ]
Oner, Hasimcan [2 ]
Asimgil, Hande [2 ]
Francey, Lauren J. [5 ,6 ]
Sancar, Aziz [4 ]
Kruger, Warren D. [7 ]
Hogenesch, John B. [3 ,5 ,6 ]
Weljie, Aalim [3 ]
Anafi, Ron C. [8 ]
Kavakli, Ibrahim Halil [1 ,2 ]
机构
[1] Koc Univ, Dept Mol Biol & Genet, Istanbul, Turkey
[2] Koc Univ, Dept Chem & Biol Engn, TR-34450 Istanbul, Turkey
[3] Univ Penn, Syst Pharmacol & Translat Therapeut, Perelman Sch Med, Philadelphia, PA 19104 USA
[4] Univ N Carolina, Dept Biochem & Biophys, Sch Med, Chapel Hill, NC 27515 USA
[5] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA
[6] Cincinnati Childrens Hosp Med Ctr, Div Immunobiol, Cincinnati, OH 45229 USA
[7] Fox Chase Canc Ctr, Canc Biol Program, 7701 Burholme Ave, Philadelphia, PA 19111 USA
[8] Univ Penn, Dept Med, Chronobiol & Sleep Inst, Perelman Sch Med, Philadelphia, PA 19104 USA
关键词
circadian rhythm; cryptochrome; cystathionine beta-synthase; metabolism; transcriptional regulation; GENE-EXPRESSION; HYDROGEN-SULFIDE; TRANSCRIPTIONAL ARCHITECTURE; RHYTHMS; EXTRACTION; TOPOLOGY; PROTEINS; DISRUPTS; MICE;
D O I
10.1111/febs.15360
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 beta-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), 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.
引用
收藏
页码:614 / 639
页数:26
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