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.

The Nuclear Receptor HIZR-1 Uses Zinc as a Ligand to Mediate Homeostasis in Response to High Zinc

“…elegans , including the zinc transporter genes cdf-2 and ttm-1b [13,14]. To identify genes that mediate this response, we screened for mutant animals that displayed abnormal regulation of cdf-2 .…”

“…elegans contains 14 cation diffusion facilitator (CDF) genes that encode transporters for zinc and possibly other metal ions. The CDF genes cdf-2 and ttm-1b are transcriptionally up-regulated in intestinal cells by high dietary zinc, and these transporters promote zinc storage and excretion [14,19]. Transcriptional activation of these genes is mediated by the high zinc activation (HZA) element, a DNA enhancer [15].…”

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

“…The regulatory function similar to CDF1 is conducted by SUR-7 (no vertebrate ZnT homologs), which is probably localized to the ER. In homeostatic control, CDF2 (a ZnT2 homolog) or TTM-1 (no vertebrate ZnT homologs) also plays a crucial role by transporting zinc into gut granules (lysosome-related organelles) or excreting zinc from the apical plasma membrane in intestinal cells, respectively (348,349).…”

SLC30A10: A novel manganese transporter

“…Roh et al showed that TTM-1B is induced by high dietary Zn and regulates Zn excretion from intestinal cells into the lumen of the gut, however, TTM-1A is not Zn regulated and its function remains unknown. 27 The RNAi bacteria we used here specifically targeted ttm-1a, but not ttm-1b. These results indicated a novel role of TTM-1A to transport Mn intracellularly.…”