Conserved function of a RasGEF-mediated pathway in the metabolic compensation of the circadian clock

Sárkány, Orsolya and Szőke, Anita and Pettkó-Szandtner, Aladár and Kálmán, Eszter Éva and Brunner, Michael and Gyöngyösi, Norbert and Káldi, Krisztina (2025) Conserved function of a RasGEF-mediated pathway in the metabolic compensation of the circadian clock. FEBS JOURNAL, 292 (20). pp. 5335-5354. ISSN 1742-464X

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Abstract

Metabolic compensation of the circadian clock ensures endogenous timing across a broad range of nutrient conditions, enabling organisms to adapt efficiently to recurrent environmental changes, even during nutrient scarcity. In this study, we have identified a novel clock-controlled gene, rasgef (Rat Sarcoma Guanine Nucleotide Exchange Factor), that plays a crucial role in modulating the circadian clock under starvation conditions in the circadian model organism Neurospora crassa. The gene product, RasGEF-a nucleotide exchange factor for the small G protein RAS2P (Rat Sarcoma 2 Protein)-displays glucose-dependent phosphorylation and localization. We show that deletion of rasgef hinders metabolic compensation of the circadian clock to glucose-depleted conditions and disrupts the rhythmic expression of the output gene ccg2. Furthermore, we demonstrate in osteosarcoma cells that the period of the mammalian clock is also compensated across a wide range of extracellular glucose levels and adaptation of the clock to glucose-starved conditions depends on the RasGEF homolog SOS1 (Son of Sevenless 1) and its downstream signaling component ERK (Extracellular Signal-Regulated Kinase). Our results suggest a conserved role of RasGEF-mediated signaling in the maintenance of circadian rhythm under glucose-limited conditions.

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