Analysis of Zinc Transporters in C. elegans

Zinc is a trace element essential for organisms, and organisms have homeostatic mechanisms to control zinc metabolism. Zinc metabolism is mediated by numerous proteins including zinc transporters, zinc-responsive transcription factors and zinc-binding proteins. Of these proteins, zinc transporters, composed of CDF and ZIP families, play a major role and are implicated in a variety of human diseases. However, the mechanisms by which zinc transporters coordinate to regulate zinc homeostasis in whole animals and by which they are related to human diseases are not well understood. To address these questions, we used C. elegans as a model system. While three C. elegans cdf genes have been characterized previously, the majority of zinc transporters remain to be studied. Here, we characterized cdf-2 and ttm-1 and conducted initial studies of other zinc transporters. We demonstrated that lysosome-related organelles in intestinal cells, termed gut granules, function as a major site of zinc storage. Gut granules were important for detoxification of excess zinc as well as mobilization of zinc in response to low-zinc environments, and CDF-2 was necessary for these processes. In high zinc conditions, gut granules displayed morphological changes characterized by a bilobed morphology with asymmetric distributions of molecules. These findings suggest novel mechanisms of zinc storage, detoxification and mobilization in C. elegans. ttm-1 encodes two isoforms, ttm-1a and ttm-1b, by using different transcription start sites. TTM-1 plays a role in the excretion of zinc and is involved in zinc detoxification via the action of TTM-1B which localizes to the apical membrane of intestinal cells. These functions of TTM-1 are critical specifically in the absence of CDF-2, suggesting that TTM-1coordinates with CDF-2 to regulate zinc homeostasis of whole animals. Studies of other zinc transporters including expression pattern analysis suggested novel functions of zinc transporters in biological processes. These results suggest that further studies of C. elegans zinc transporters may contribute to understanding of sophisticated networks of zinc transporters in zinc metabolism and elucidate physiological functions of zinc transporters