RESUMO
Type III galactosemia is a metabolic disorder caused by reduced activity of UDP-galactose-4-epimerase, which participates in galactose metabolism and the generation of various UDP-sugar species. We characterized gale-1 in Caenorhabditis elegans and found that a complete loss-of-function mutation is lethal, as has been hypothesized for humans, whereas a nonlethal partial loss-of-function allele causes a variety of developmental abnormalities, likely resulting from the impairment of the glycosylation process. We also observed that gale-1 mutants are hypersensitive to galactose as well as to infections. Interestingly, we found interactions between gale-1 and the unfolded protein response.
Assuntos
Caenorhabditis elegans/genética , Galactosemias/genética , Galactosemias/metabolismo , Animais , Caenorhabditis elegans/embriologia , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Desintegrinas/metabolismo , Hexosaminas/metabolismo , Redes e Vias Metabólicas , Metaloendopeptidases/metabolismo , Morfogênese/genética , Mutação , Fenótipo , Transporte Proteico , Transdução de Sinais , UDPglucose-Hexose-1-Fosfato Uridiltransferase/deficiência , UDPglucose-Hexose-1-Fosfato Uridiltransferase/genética , Resposta a Proteínas não Dobradas , Açúcares de Uridina Difosfato/metabolismoRESUMO
In Caenorhabditis elegans, the insulin/IGF pathway participates in the decision to initiate dauer development. Dauer is a diapause stage that is triggered by environmental stresses, such as a lack of nutrients. Insulin/IGF receptor mutants arrest constitutively in dauer, an effect that can be suppressed by mutations in other elements of the insulin/IGF pathway or by a reduction in the activity of the nuclear hormone receptor daf-12. We have isolated a pkc-1 mutant that acts as a novel suppressor of the dauer phenotypes caused by insulin/IGF receptor mutations. Interactions between insulin/IGF mutants and the pkc-1 suppressor mutant are similar to those described for daf-12 or the DAF-12 coregulator din-1. Moreover, we show that the expression of the DAF-12 target daf-9, which is normally elevated upon a reduction in insulin/IGF receptor activity, is suppressed in a pkc-1 mutant background, suggesting that pkc-1 could link the daf-12 and insulin/IGF pathways. pkc-1 has been implicated in the regulation of peptide neurosecretion in C. elegans. Although we demonstrate that pkc-1 expression in the nervous system regulates dauer formation, our results suggest that the requirement for pkc-1 in neurosecretion is independent of its role in modulating insulin/IGF signalling. pkc-1 belongs to the novel protein kinase C (nPKC) family, members of which have been implicated in insulin resistance and diabetes in mammals, suggesting a conserved role for pkc-1 in the regulation of the insulin/IGF pathway.