Published January 1, 2021
| Version v1
Journal article
Open
CRY1-CBS binding regulates circadian clock function and metabolism
Creators
- 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. Fox Chase Canc Ctr, Canc Biol Program, 7701 Burholme Ave, Philadelphia, PA 19111 USA
- 6. Univ Penn, Dept Med, Chronobiol & Sleep Inst, Perelman Sch Med, Philadelphia, PA 19104 USA
Description
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.
Files
bib-6ef0829e-b091-4184-a953-32b2c71e869b.txt
Files
(310 Bytes)
| Name | Size | Download all |
|---|---|---|
|
md5:1341999cda48da3708ecace220554119
|
310 Bytes | Preview Download |