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Cell Rep. 2017 Apr 11;19(2):255-266. doi: 10.1016/j.celrep.2017.03.041.

FAD Regulates CRYPTOCHROME Protein Stability and Circadian Clock in Mice.

Author information

1
Department of Neurology, University of California, San Francisco, CA 94143, USA.
2
UCLA Metabolomics Center, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA.
3
Department of Neurology, University of California, San Francisco, CA 94143, USA; Weill Neuroscience of Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: ying-hui.fu@ucsf.edu.
4
Department of Neurology, University of California, San Francisco, CA 94143, USA; Weill Neuroscience of Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA 94143, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: ljp@ucsf.edu.

Abstract

The circadian clock generates biological rhythms of metabolic and physiological processes, including the sleep-wake cycle. We previously identified a missense mutation in the flavin adenine dinucleotide (FAD) binding pocket of CRYPTOCHROME2 (CRY2), a clock protein that causes human advanced sleep phase. This prompted us to examine the role of FAD as a mediator of the clock and metabolism. FAD stabilized CRY proteins, leading to increased protein levels. In contrast, knockdown of Riboflavin kinase (Rfk), an FAD biosynthetic enzyme, enhanced CRY degradation. RFK protein levels and FAD concentrations oscillate in the nucleus, suggesting that they are subject to circadian control. Knockdown of Rfk combined with a riboflavin-deficient diet altered the CRY levels in mouse liver and the expression profiles of clock and clock-controlled genes (especially those related to metabolism including glucose homeostasis). We conclude that light-independent mechanisms of FAD regulate CRY and contribute to proper circadian oscillation of metabolic genes in mammals.

KEYWORDS:

CRY; CRYPTOCHROME; FAD; FBXL3; Riboflavin kinase; circadian clock; circadian rhythms; metabolism; protein degradation

Comment in

PMID:
28402850
PMCID:
PMC5423466
DOI:
10.1016/j.celrep.2017.03.041
[Indexed for MEDLINE]
Free PMC Article

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