CRY1-CBS binding regulates circadian clock function and metabolism

FEBS J. 2021 Jan;288(2):614-639. doi: 10.1111/febs.15360. Epub 2020 Jun 9.

Abstract

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 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.

Keywords: circadian rhythm; cryptochrome; cystathionine β-synthase; metabolism; transcriptional regulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism
  • Amino Acid Sequence
  • Animals
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism
  • Circadian Clocks / genetics*
  • Circadian Rhythm / genetics*
  • Cryptochromes / deficiency
  • Cryptochromes / genetics*
  • Cystathionine beta-Synthase / genetics*
  • Cystathionine beta-Synthase / metabolism
  • E-Box Elements
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Metabolic Networks and Pathways / genetics
  • Metabolome / genetics*
  • Mice
  • Mice, Knockout
  • Mutation
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / metabolism
  • Protein Binding
  • Protein Processing, Post-Translational*
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Signal Transduction

Substances

  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Cry1 protein, mouse
  • Cry2 protein, mouse
  • Cryptochromes
  • Per1 protein, mouse
  • Period Circadian Proteins
  • CLOCK Proteins
  • Clock protein, mouse
  • Cystathionine beta-Synthase