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.
NF-E2–related factor 2 (NRF2) transcription factor has a fundamental role in cell homeostasis maintenance as one of the master regulators of oxidative and electrophilic stress responses. Previous studies have shown that a regulatory connection exists between NRF2 and autophagy during reactive oxygen species–generated oxidative stress. The aim of the present study was to investigate how autophagy is turned off during prolonged oxidative stress, to avoid overeating and destruction of essential cellular components. AMPK is a key cellular energy sensor highly conserved in eukaryotic organisms, and it has an essential role in autophagy activation at various stress events. Here the role of human AMPK and its Caenorhabditis elegans counterpart AAK-2 was explored upon oxidative stress. We investigated the regulatory connection between NRF2 and AMPK during oxidative stress induced by tert-butyl hydroperoxide (TBHP) in HEK293T cells and C. elegans. Putative conserved NRF2/protein skinhead-1 binding sites were found in AMPK/aak-2 genes by in silico analysis and were later confirmed experimentally by using EMSA. After addition of TBHP, NRF2 and AMPK showed a quick activation; AMPK was later down-regulated, however, while NRF2 level remained high. Autophagosome formation and Unc-51–like autophagy activating kinase 1 phosphorylation were initially stimulated, but they returned to basal values after 4 h of TBHP treatment. The silencing of NRF2 resulted in a constant activation of AMPK leading to hyperactivation of autophagy during oxidative stress. We observed the same effects in C. elegans demonstrating the conservation of this self-defense mechanism to save cells from hyperactivated autophagy upon prolonged oxidative stress. We conclude that NRF2 negatively regulates autophagy through delayed down-regulation of the expression of AMPK upon prolonged oxidative stress. This regulatory connection between NRF2 and AMPK may have an important role in understanding how autophagy is regulated in chronic human morbidities characterized by oxidative stress, such as neurodegenerative diseases, certain cancer types, and in metabolic diseases.—Kosztelnik, M., Kurucz, A., Papp, D., Jones, E., Sigmond, T., Barna, J., Traka, M. H., Lorincz, T., Szarka, A., Banhegyi, G., Vellai, T., Korcsmaros, T., Kapuy, O. Suppression of AMPK/aak-2 by NRF2/SKN-1 down-regulates autophagy during prolonged oxidative stress.
SummaryA fascinating aspect of sexual dimorphism in various animal species is that the two sexes differ substantially in lifespan. In humans, for example, women's life expectancy exceeds that of men by 3–7 years. Whether this trait can be attributed to dissimilar lifestyles or genetic (regulatory) factors remains to be elucidated. Herein, we demonstrate that in the nematode Caenorhabditis elegans, the significantly longer lifespan of hermaphrodites—which are essentially females capable of sperm production—over males is established by TRA‐1, the terminal effector of the sex‐determination pathway. This transcription factor directly controls the expression of daf‐16/FOXO, which functions as a major target of insulin/IGF‐1 signaling (IIS) and key modulator of aging across diverse animal phyla. TRA‐1 extends hermaphrodite lifespan through promoting daf‐16 activity. Furthermore, TRA‐1 also influences reproductive growth in a DAF‐16‐dependent manner. Thus, the sex‐determination machinery is an important regulator of IIS in this organism. These findings provide a mechanistic insight into how longevity and development are specified unequally in the two genders. As TRA‐1 is orthologous to mammalian GLI (glioma‐associated) proteins, a similar sex‐specific mechanism may also operate in humans to determine lifespan.
The regeneration of paired appendages in certain fish and amphibian lineages is a well established and extensively studied regenerative phenomenon. The teleost fin is comprised of a proximal endoskeletal part (considered homologous to the Tetrapod limb) and a distal exoskeletal one, and these two parts form their bony elements through different ossification processes. In the past decade, a significant body of literature has been generated about the biology of exoskeletal regeneration in zebrafish. However, it is still not clear if this knowledge can be applied to the regeneration of endoskeletal parts. To address this question, we decided to compare endo- and exoskeletal regenerative capacity in zebrafish (Danio rerio) and mudskippers (Periophthalmus barbarous). In contrast to the reduced endoskeleton of zebrafish, Periophthalmus has well developed pectoral fins with a large and easily accessible endoskeleton. We performed exo- and endoskeletal amputations in both species and followed the regenerative processes. Unlike the almost flawless exoskeletal regeneration observed in zebrafish, regeneration following endoskeletal amputation is often impaired in this species. This difference is even more pronounced in Periophthalmus where we could observe no regeneration in endoskeletal structures. Therefore, regeneration is regulated differentially in the exo- and endoskeleton of teleost species.
Females and males differ substantially in various neuronal functions in divergent, sexually dimorphic animal species, including humans. Despite its developmental, physiological and medical significance, understanding the molecular mechanisms by which sex-specific differences in the anatomy and operation of the nervous system are established remains a fundamental problem in biology. Here, we show that in Caenorhabditis elegans (nematodes), the global sex-determining factor TRA-1 regulates food leaving (mate searching), male mating and adaptation to odorants in a sex-specific manner by repressing the expression of goa-1 gene, which encodes the Gα (i/o) subunit of heterotrimeric G (guanine-nucleotide binding) proteins triggering physiological responses elicited by diverse neurotransmitters and sensory stimuli. Mutations in tra-1 and goa-1 decouple behavioural patterns from the number of X chromosomes. TRA-1 binds to a conserved binding site located in the goa-1 coding region, and downregulates goa-1 expression in hermaphrodites, particularly during embryogenesis when neuronal development largely occurs. These data suggest that the sex-determination machinery is an important modulator of heterotrimeric G protein-mediated signalling and thereby various neuronal functions in this organism and perhaps in other animal phyla.
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