title: ttm-1 encodes CDF transporters that excrete zinc from intestinal cells of C. elegans and act in a parallel negative feedback circuit that promotes homeostasis.
abstract: Zinc is an essential metal involved in a wide range of biological processes, and aberrant zinc metabolism is implicated in human diseases. The gastrointestinal tract of animals is a critical site of zinc metabolism that is responsible for dietary zinc uptake and distribution to the body. However, the role of the gastrointestinal tract in zinc excretion remains unclear. Zinc transporters are key regulators of zinc metabolism that mediate the movement of zinc ions across membranes. Here, we identified a comprehensive list of 14 predicted Cation Diffusion Facilitator (CDF) family zinc transporters in Caenorhabditis elegans and demonstrated that zinc is excreted from intestinal cells by one of these CDF proteins, TTM-1B. The ttm-1 locus encodes two transcripts, ttm-1a and ttm-1b, that use different transcription start sites. ttm-1b expression was induced by high levels of zinc specifically in intestinal cells, whereas ttm-1a was not induced by zinc. TTM-1B was localized to the apical plasma membrane of intestinal cells, and analyses of loss-of-function mutant animals indicated that TTM-1B promotes zinc excretion into the intestinal lumen. Zinc excretion mediated by TTM-1B contributes to zinc detoxification. These observations indicate that ttm-1 is a component of a negative feedback circuit, since high levels of cytoplasmic zinc increase ttm-1b transcript levels and TTM-1B protein functions to reduce the level of cytoplasmic zinc. We showed that TTM-1 isoforms function in tandem with CDF-2, which is also induced by high levels of cytoplasmic zinc and reduces cytoplasmic zinc levels by sequestering zinc in lysosome-related organelles. These findings define a parallel negative feedback circuit that promotes zinc homeostasis and advance the understanding of the physiological roles of the gastrointestinal tract in zinc metabolism in animals.
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Hyun Cheol
authors.initials: HC
authors.lastname: Roh
authors.forename: Sara
authors.initials: S
authors.lastname: Collier
authors.forename: Krupa
authors.initials: K
authors.lastname: Deshmukh
authors.forename: James
authors.initials: J
authors.lastname: Guthrie
authors.forename: J David
authors.initials: JD
authors.lastname: Robertson
authors.forename: Kerry
authors.initials: K
authors.lastname: Kornfeld
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D006706:Homeostasis; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology; D017136:Ion Transport / Q000235:genetics; D008247:Lysosomes / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics*; D010802:Phylogeny; D020033:Protein Isoforms / Q000235:genetics; D015032:Zinc / Q000378:metabolism*
chemical_list: C546713:CDF-2 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D027682:Cation Transport Proteins; D026901:Membrane Transport Proteins; D020033:Protein Isoforms; C583316:Ttm-1 protein, C elegans; C017800:zinc-binding protein; D015032:Zinc