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2013学年秋季学期系列学术讲座之九
题目：Genetics of the human circadian system and direct links to metabolism
报告人：Louis J. Ptáček
美国国家科学院院士
John C. Coleman Distinguished Professor of Neurology,
Director, Division of Neurogenetics, University of California at San Francisco,
Investigator, Howard Hughes Medical Institute
时间：2013年11月22日（周五），下午13:00-14:30 PM
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Posttranslational modifications play central roles in myriad biological pathways including circadian regulation. We employed a circadian proteomic approach to demonstrate that circadian timing of phosphorylation is a critical factor in regulating complex GSK3b-dependent pathways and identified O-GlcNAc transferase (OGT) as a substrate of GSK3b. Interestingly, OGT activity is regulated by GSK3b; hence, OGT and GSK3b exhibit reciprocal regulation. Modulating O-GlcNAcylation levels alter circadian period length in both mice and Drosophila; conversely, protein O-GlcNAcylation is circadianly regulated. Central clock proteins, Clock and Period, are reversibly modified by O- GlcNAcylation to regulate their transcriptional activities. In addition, O-GlcNAcylation of a region in PER2 known to regulate human sleep phase (S662–S674) competes with phosphorylation of this region, and this interplay is at least partly mediated by glucose levels. Together, these results indicate that O-GlcNAcylation serves as a metabolic sensor for clock regulation and works coordinately with phosphorylation to fine-tune circadian clock.
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