CRY1-CBS binding regulates circadian clock function and metabolism.
CRY1-CBS binding regulates circadian clock function and metabolism.
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DOI：
10.1111/febs.15360
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Kavakli IH
中科院分区：
文献类型：
--
作者：
Cal-Kayitmazbatir S;Kulkoyluoglu-Cotul E;Growe J;Selby CP;Rhoades SD;Malik D;Oner H;Asimgil H;Francey LJ;Sancar A;Kruger WD;Hogenesch JB;Weljie A;Anafi RC;Kavakli IH
昼夜节律紊乱影响代谢健康。新陈代谢调节昼夜节律功能。然而，耦合昼夜节律和代谢的机制仍然知之甚少。在这里，我们报告，胱硫醚β-合酶（CBS），在一个碳代谢的中心酶，功能与核心昼夜蛋白Cryptochrome 1（CYP 1）相互作用。在细胞中，CBS增强了CLOCK/BMAL 1复合物的抑制作用，并缩短了昼夜节律周期。值得注意的是，我们发现突变型CBS-I278 T蛋白，最常见的原因同型胱氨酸尿症，不结合β 1或调节其阻遏活性。转基因CbsZn/Zn小鼠在维持昼夜运动活动期的同时，表现出降低的昼夜动力和增加的E-BOX输出表达。CBS的功能受到BMP 1结合的间接影响。β 1调节CBS的酶活性。来自Cry 1 −/−小鼠的肝脏提取物显示出降低的CBS活性，在添加外源性野生型（WT）Rx 1后恢复正常。WT、CbsZn/Zn、Cry 1 −/−和Cry 2 −/−样本的代谢组学分析突出了内源性β 1的代谢重要性。我们观察到的一个碳和transsulfation途径的时间变化归因于BTA 1诱导的CBS激活。CBS-BS 1结合提供了一个翻译后开关，以调节细胞的昼夜生理和代谢控制。昼夜节律和代谢的耦合机制仍然知之甚少。我们发现，核心昼夜节律蛋白隐花色素1（Cryptochrome 1）结合胱硫醚β-合酶（CBS），一个在一碳代谢的中心酶。这种结合调节两种蛋白质的活性。在活跃期，CBS增强了BMAL 1/CLOCK驱动的转录的BMAL 1介导的抑制。在静息期，BMP 1增加CBS酶活性。
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 CbsZn/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, CbsZn/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. The mechanisms coupling circadian rhythms and metabolism remain poorly understood. We find that the core circadian protein Cryptochrome 1 (CRY1) binds Cystathionine β-synthase (CBS), a central enzyme in one-carbon metabolism. This binding modulates the activity of both proteins. During the active phase, CBS augments CRY1 mediated repression of BMAL1/CLOCK driven transcription. During the rest phase, CRY1 increases CBS enzymatic activity.
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DOI：
10.1073/pnas.1619320114
发表时间：
2017-05-16
影响因子：
11.1
作者：
Anafi, Ron C.;Francey, Lauren J.;Kim, Junhyong
通讯作者：
Kim, Junhyong
影响因子：
14.9
作者：
Geer LY;Marchler-Bauer A;Geer RC;Han L;He J;He S;Liu C;Shi W;Bryant SH
通讯作者：
Bryant SH
影响因子：
64.8
作者：
La Manno G;Soldatov R;Zeisel A;Braun E;Hochgerner H;Petukhov V;Lidschreiber K;Kastriti ME;Lönnerberg P;Furlan A;Fan J;Borm LE;Liu Z;van Bruggen D;Guo J;He X;Barker R;Sundström E;Castelo-Branco G;Cramer P;Adameyko I;Linnarsson S;Kharchenko PV
通讯作者：
Kharchenko PV
影响因子：
3.8
作者：
Kruger WD
通讯作者：
Kruger WD
影响因子：
14.9
作者：
Jewison T;Su Y;Disfany FM;Liang Y;Knox C;Maciejewski A;Poelzer J;Huynh J;Zhou Y;Arndt D;Djoumbou Y;Liu Y;Deng L;Guo AC;Han B;Pon A;Wilson M;Rafatnia S;Liu P;Wishart DS
通讯作者：
Wishart DS