Abstract
BackgroundTemperature affects virtually all cellular processes. A quick increase in temperature challenges the cells to undergo a heat shock response to maintain cellular homeostasis. Heat shock factor-1 (HSF-1) functions as a major player in this response as it activates the transcription of genes coding for molecular chaperones (also called heat shock proteins) that maintain structural integrity of proteins. However, the mechanisms by which HSF-1 adjusts fundamental cellular processes such as growth, proliferation, differentiation and aging to the ambient temperature remain largely unknown.ResultsWe demonstrate here that in Caenorhabditis elegans HSF-1 represses the expression of daf-7 encoding a TGF-β (transforming growth factor-beta) ligand, to induce young larvae to enter the dauer stage, a developmentally arrested, non-feeding, highly stress-resistant, long-lived larval form triggered by crowding and starvation. Under favorable conditions, HSF-1 is inhibited by crowding pheromone-sensitive guanylate cyclase/cGMP (cyclic guanosine monophosphate) and systemic nutrient-sensing insulin/IGF-1 (insulin-like growth factor-1) signaling; loss of HSF-1 activity allows DAF-7 to promote reproductive growth. Thus, HSF-1 interconnects the insulin/IGF-1, TGF-β and cGMP neuroendocrine systems to control development and longevity in response to diverse environmental stimuli. Furthermore, HSF-1 upregulates another TGF-β pathway-interacting gene, daf-9/cytochrome P450, thereby fine-tuning the decision between normal growth and dauer formation.ConclusionTogether, these results provide mechanistic insight into how temperature, nutrient availability and population density coordinately influence development, lifespan, behavior and stress response through HSF-1.
Highlights
We found that Heat shock factor-1 (HSF-1) function is required for daf-7 repression in animals defective for DAF-11: daf-11(−); hsf-1(−) double mutants displayed nearly wild-type levels of daf-7 expression (Figure 1B, C)
In this study we identified two C. elegans TGF-β pathway-related genes, daf-7/TGF-β and daf-9/cytochrome P450, whose regulatory regions contain a conserved binding site for HSF-1 (Figures 2A, B and 4B, C), and whose expression highly depends on HSF-1 activity (Figures 1B, C, 2D and 4D). daf-7 and daf-9 are likely to be under the direct control of HSF-1. daf-7 expression is repressed, while daf-9 expression is upregulated, by HSF-1, resulting in opposite effects on dauer formation
Fundamental insights into how genes and environmental factors influence metazoan metabolism, development and aging have emerged from a genetic dissection of the C. elegans dauer diapause, which is an arrested, long-lived, and highly stress-resistant larval form triggered by starvation and crowding
Summary
In the nematode Caenorhabditis elegans the insulin/IGF-1 and TGF-β signaling pathways co-regulate metabolism, aging, stress tolerance and development [1,2,3,4,5]. HSF-1 becomes activated via trimerization and phosphorylation, translocates into the nucleus to promote the transcription of genes that encode heat shock proteins (HSPs) such as Hsp, Hsp, and Hsp90 [12,13,14]. These factors largely contribute to the protection of cells from proteindamaging stress.
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