RESUMO
Protein homeostasis (proteostasis) networks are dynamic throughout the lifespan of an organism. During Caenorhabditis elegans adulthood, the maintenance of metastable proteins and the activation of stress responses are inversely associated with germline stem cell proliferation. Here, we employed the thymidylate synthase inhibitor 5-fluoro-2'-deoxyuridine (FUdR) to chemically inhibit reproduction, thus allowing for examination of the interplay between reproduction and somatic proteostasis. We found that treatment with FUdR modulates proteostasis decline both before and after reproduction onset, such that effective induction of the heat shock response was maintained during adulthood and that metastable temperature-sensitive mutant phenotypes were rescued under restrictive conditions. However, FUdR treatment also improved the folding capacity of germline- and gonadogenesis-defective mutants, suggesting that proteostasis modulation by FUdR is independent of germline stem cell proliferation or inhibition of reproduction. Our data, therefore, indicate that FUdR converges on alternative regulatory signals that modulate C. elegans proteostasis capacity during development and adulthood.
Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Floxuridina/farmacologia , Dobramento de Proteína/efeitos dos fármacos , Envelhecimento/efeitos dos fármacos , Animais , Células Germinativas/efeitos dos fármacos , Células Germinativas/metabolismo , Gônadas/efeitos dos fármacos , Gônadas/metabolismo , Resposta ao Choque Térmico/efeitos dos fármacos , Mutação/genética , Reprodução/efeitos dos fármacos , TemperaturaRESUMO
The long-term health of all metazoan cells is linked to protein quality control, which is achieved by proteostasis, a complex network of molecular interactions that determines the health of the proteome under physiological or stress conditions. Studying the regulation of cellular proteostasis in the context of the whole organism has unraveled multiple layers of cell-nonautonomous regulation, including neuronal regulation, cell-to-cell stress signals and endocrine signaling that affect growth, development and aging. Here, we discuss emerging concepts in cell-nonautonomous regulation of protein quality control networks. The identification of organismal modulators of cellular proteostasis may present novel, yet general targets for misfolding disease intervention.
