Integration of carbohydrate metabolism and redox state controls dauer larva formation in Caenorhabditis elegans

Abstract

Under adverse conditions, Caenorhabditis elegans enters a diapause stage called the dauer larva. External cues signal the nuclear hormone receptor DAF-12, the activity of which is regulated by its ligands: dafachronic acids (DAs). DAs are synthesized from cholesterol, with the last synthesis step requiring NADPH, and their absence stimulates dauer formation. Here we show that NADPH levels determine dauer formation in a regulatory mechanism involving key carbohydrate and redox metabolic enzymes. Elevated trehalose biosynthesis diverts glucose-6-phosphate from the pentose phosphate pathway, which is the major source of cellular NADPH. This enhances dauer formation due to the decrease in the DA level. Moreover, DAF-12, in cooperation with DAF-16/FoxO, induces negative feedback of DA synthesis via activation of the trehalose-producing enzymes TPS-1/2 and inhibition of the NADPH-producing enzyme IDH-1. Thus, the dauer developmental decision is controlled by integration of the metabolic flux of carbohydrates and cellular redox potential.

Plant-parasitic nematodes: towards understanding molecular players in stress responses

“…More generally, it was shown that DAF-16 and the IIS pathway are at the crossroads of redox and metabolism in C. elegans (Penkov et al , 2015). This finding supports the hypothesis that there are developmental checkpoints in C. elegans in accordance with the model ‘ should I stay/should I go ’ (Murphy and Hu, 2013; Schindler and Sherwood, 2014).…”

“…Downstream of the stimulus perception, oxidative stress response is modulated by evolutionary conserved signalling pathways in the animal kingdom (Shivers et al , 2008; van der Hoeven et al , 2011; Shore and Ruvkun, 2013; Blackwell et al , 2015; Klotz et al , 2015; Penkov et al , 2015). In a general manner, the regulation of DAF-16 and SKN-1 involves an intricate network of post-translational modifications and protein–protein interactions.…”

Small-molecule pheromones and hormones controlling nematode development

“…79,80 Interestingly, the metabolic changes that occur with dauer formation lead to decreased NADPH levels and may also represent a mechanism to inhibit dafachonic acid biosynthesis, given that DAF-9 is NADPH dependent. 18 Specifically, the increased trehalose biosynthesis that comes with dauer formation diverts glucose-6-phosphate from the pentose phosphate pathway, a major contributor to cellular NADPH levels, thereby reducing cellular NADPH levels and indirectly inhibiting dafachronic acid biosynthesis to promote dauer formation. 18 …”

“…18 Specifically, the increased trehalose biosynthesis that comes with dauer formation diverts glucose-6-phosphate from the pentose phosphate pathway, a major contributor to cellular NADPH levels, thereby reducing cellular NADPH levels and indirectly inhibiting dafachronic acid biosynthesis to promote dauer formation. 18 …”

“…16,17 The glucose is also diverted to the biosynthesis of trehalose, which provides osmotic protection against dessication. 16,18,19 C. elegans can survive as a dauer for up to several months, and only begins to die once its fat stores become depleted. 15 The stress resistance of the dauer is due in part to altered gene expression in which genes involved in starvation, heat, and oxidative stress are up-regulated.…”