title: The Intestinal Copper Exporter CUA-1 Is Required for Systemic Copper Homeostasis in Caenorhabditis elegans.
abstract: Copper plays key catalytic and regulatory roles in biochemical processes essential for normal growth, development, and health. Defects in copper metabolism cause Menkes and Wilson's disease, myeloneuropathy, and cardiovascular disease and are associated with other pathophysiological states. Consequently, it is critical to understand the mechanisms by which organisms control the acquisition, distribution, and utilization of copper. The intestinal enterocyte is a key regulatory point for copper absorption into the body; however, the mechanisms by which intestinal cells transport copper to maintain organismal copper homeostasis are poorly understood. Here, we identify a mechanism by which organismal copper homeostasis is maintained by intestinal copper exporter trafficking that is coordinated with extraintestinal copper levels in Caenorhabditis elegans Specifically, we show that CUA-1, the C. elegans homolog of ATP7A/B, localizes to lysosome-like organelles (gut granules) in the intestine under copper overload conditions for copper detoxification, whereas copper deficiency results in a redistribution of CUA-1 to basolateral membranes for copper efflux to peripheral tissues. Worms defective in gut granule biogenesis exhibit defects in copper sequestration and increased susceptibility to toxic copper levels. Interestingly, however, a splice isoform CUA-1.2 that lacks a portion of the N-terminal domain is targeted constitutively to the basolateral membrane irrespective of dietary copper concentration. Our studies establish that CUA-1 is a key intestinal copper exporter and that its trafficking is regulated to maintain systemic copper homeostasis. C. elegans could therefore be exploited as a whole-animal model system to study regulation of intra- and intercellular copper trafficking pathways.
authors.affiliation: From the Department of Animal and Avian Sciences.
authors.forename: Haarin
authors.initials: H
authors.lastname: Chun
authors.affiliation: From the Department of Animal and Avian Sciences.
authors.forename: Anuj Kumar
authors.initials: AK
authors.lastname: Sharma
authors.affiliation: the Redox Biology Center, Department of Biochemistry, University of Nebraska, Lincoln, Nebraska 68588, and.
authors.forename: Jaekwon
authors.initials: J
authors.lastname: Lee
authors.affiliation: the Department of Chemistry, University of California at Berkeley, Berkeley, California 94720.
authors.forename: Jefferson
authors.initials: J
authors.lastname: Chan
authors.affiliation: the Department of Chemistry, University of California at Berkeley, Berkeley, California 94720.
authors.forename: Shang
authors.initials: S
authors.lastname: Jia
authors.affiliation: From the Department of Animal and Avian Sciences, bekim@umd.edu.|Biological Sciences Graduate Program, University of Maryland, College Park, Maryland 20742.
authors.forename: Byung-Eun
authors.initials: BE
authors.lastname: Kim
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D017173:Caenorhabditis elegans / Q000254:growth & development / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D003300:Copper / Q000378:metabolism*; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000254:growth & development; D021381:Protein Transport
chemical_list: D029742:Caenorhabditis elegans Proteins; D027682:Cation Transport Proteins; D003300:Copper; D000251:Adenosine Triphosphatases
keywords: CUA-1; Caenorhabditis elegans (C. elegans); copper transport; intestine; membrane trafficking; metal homeostasis