O-GlcNAcylation of PERIOD regulates its interaction with CLOCK and timing of circadian transcriptional repression
| Autor: | Haiyan Zheng, Joanna C. Chiu, Jens T. Vanselow, Ying H. Li, Andreas Schlosser, Xianhui Liu |
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| Přispěvatelé: | Taghert, Paul H |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Cancer Research
Protein Extraction Circadian clock Gene Expression CLOCK Proteins QH426-470 Biochemistry Transcriptome 0302 clinical medicine Drosophila Proteins Developmental Post-Translational Modification Phosphorylation Genetics (clinical) Extraction Techniques 0303 health sciences Chronobiology Drosophila Melanogaster Eukaryota Gene Expression Regulation Developmental Animal Models Period Circadian Proteins Precipitation Techniques Circadian Rhythm Cell biology Insects Circadian Oscillators Circadian Rhythms Experimental Organism Systems Drosophila Drosophila melanogaster Sleep Research Entrainment (chronobiology) Research Article Arthropoda 1.1 Normal biological development and functioning Biology Research and Analysis Methods 03 medical and health sciences Model Organisms Underpinning research Circadian Clocks DNA-binding proteins Zeitgeber Genetics Immunoprecipitation Animals Gene Regulation Circadian rhythm Molecular Biology Psychological repression Protein Processing Metabolic and endocrine Ecology Evolution Behavior and Systematics Nutrition 030304 developmental biology Organisms Post-Translational Biology and Life Sciences Proteins biology.organism_classification Invertebrates Regulatory Proteins Gene Expression Regulation Animal Studies Generic health relevance Protein Processing Post-Translational 030217 neurology & neurosurgery Transcription Factors Developmental Biology |
| Zdroj: | Li, Ying H; Liu, Xianhui; Vanselow, Jens T; Zheng, Haiyan; Schlosser, Andreas; & Chiu, Joanna C. (2019). O-GlcNAcylation of PERIOD regulates its interaction with CLOCK and timing of circadian transcriptional repression.. PLoS genetics, 15(1), e1007953. doi: 10.1371/journal.pgen.1007953. UC Davis: Retrieved from: http://www.escholarship.org/uc/item/54c4t2d1 PLoS Genetics, Vol 15, Iss 1, p e1007953 (2019) PLoS genetics, vol 15, iss 1 PLoS Genetics |
| Popis: | Circadian clocks coordinate time-of-day-specific metabolic and physiological processes to maximize organismal performance and fitness. In addition to light and temperature, which are regarded as strong zeitgebers for circadian clock entrainment, metabolic input has now emerged as an important signal for clock entrainment and modulation. Circadian clock proteins have been identified to be substrates of O-GlcNAcylation, a nutrient sensitive post-translational modification (PTM), and the interplay between clock protein O-GlcNAcylation and other PTMs is now recognized as an important mechanism by which metabolic input regulates circadian physiology. To better understand the role of O-GlcNAcylation in modulating clock protein function within the molecular oscillator, we used mass spectrometry proteomics to identify O-GlcNAcylation sites of PERIOD (PER), a repressor of the circadian transcriptome and a critical biochemical timer of the Drosophila clock. In vivo functional characterization of PER O-GlcNAcylation sites indicates that O-GlcNAcylation at PER(S942) reduces interactions between PER and CLOCK (CLK), the key transcriptional activator of clock-controlled genes. Since we observe a correlation between clock-controlled daytime feeding activity and higher level of PER O-GlcNAcylation, we propose that PER(S942) O-GlcNAcylation during the day functions to prevent premature initiation of circadian repression phase. This is consistent with the period-shortening behavioral phenotype of per(S942A) flies. Taken together, our results support that clock-controlled feeding activity provides metabolic signals to reinforce light entrainment to regulate circadian physiology at the post-translational level. The interplay between O-GlcNAcylation and other PTMs to regulate circadian physiology is expected to be complex and extensive, and reach far beyond the molecular oscillator. Author summary Circadian clocks are self-sustained, endogenous pacemakers that enable organisms to anticipate daily environmental changes and resource abundance to perform specific time-of-day activities and achieve optimal survival. Multiple time cues are interpreted by circadian clocks to facilitate synchrony between organisms and their environment. A large body of work have identified light and temperature as important zeitgebers. More recent works highlight the significance of metabolic cues as signals to entrain and modulate circadian clocks to drive proper rhythms of physiology and behavior. Metabolic input, primarily through clock-controlled feeding activity, can regulate circadian physiology through multiple pathways. Some of these pathways are unknown while others, such as the O-GlcNAcylation of clock proteins, are just emerging. In this study, we utilized mass spectrometry proteomics to identify O-GlcNAcylation sites of the Drosophila PERIOD (PER) protein, a key regulator of the clock, and performed site-specific functional characterization of PER O-GlcNAcylation. Our results support that PER(Ser942) O-GlcNAcylation, a nutrient-sensitive protein modification that is expected to be more abundant during feeding period, prevents newly synthesized PER from prematurely performing its function during daytime and therefore restricts its activity to nighttime when flies are fasting. This study provides new insights into the mechanisms linking nutrient input and circadian physiology. |
| Databáze: | OpenAIRE |
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