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-offunction 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.G ALACTOSE is universally metabolized by three conserved enzymes that constitute the Leloir pathway ( Figure 1) (Holden et al. 2003). UDP-galactose-4-epimerase (GALE) participates in the third step of the galactose metabolism pathway, catalyzing the interconversion of UDP-galactose (UDP-gal) and UDP-glucose (UDP-glc) and in some species, including humans, also the interconversion of UDP-N-acetylgalactosamine (UDP-galNAc) and UDP-N-acetylglucosamine (UDP-glcNAc) (Figure 1) (Maley and Maley 1959;Piller et al. 1983;Kingsley et al. 1986;Wohlers et al. 1999). Thus, GALE is essential not only to use galactose as an energy source but also to produce the different species of UDP sugars required for the glycosylation of proteins and lipids.In humans, mutations in GALE result in an autosomal recessive disorder known as type III galactosemia (OMIM #230350) (Fridovich-Keil 2006;Timson 2006), a rare disease characterized by the inability to metabolize galactose with symptoms that can include early onset cataracts, liver damage, deafness, and mental retardation (Walter et al. 1999). These symptoms are thought to occur as a result of the accumulation of intermediary galactose metabolites and the reduction of UDP-sugar species, which are needed for glycosylation. Other types of galactosemia are treated with a galactose-free diet. However, because of the dual role of GALE, patients with type III galactosemia are recommended to follow a galactoserestricted diet to avoid UDP-gal deficiency. This diet only partially alleviates the severe symptoms of galactosemia type III (Walter et al. 1999), and it has been proposed that patients receive UDP-galNAc as an additional treatment (Kingsley et al. 1986).Traditional model systems to study type III galactosemia include yeast, which does not exhibit the interconversion of UDP-N acetylgalactosamine and UDP-N acetylglucosamine (Schulz et al. 2004), and cell lines, such as human fibroblasts and the ldlD cell line derived from Chinese hamster ovaries. The latter exhibits a complete loss of GALE activity, resulting in the abnormal processing of both N-and O-linked glycoproteins (Kingsley et al. 1986;Krieger et al. 1989;Slepak et al. 2007). Recently, the first multicellular model for this disease was generated in Drosophila, in which the deletion of GALE caused a lethal phenotype (Sanders et al. 2010). In t...

SummaryIn 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.