The intestinal copper exporter CUA-1 is required for systemic copper homeostasis in Caenorhabditis elegans

Haarin Chun, Anuj Kumar Sharma, Jaekwon Lee, Jefferson Chan, Shang Jia, Byung Eun Kim

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1-14
Number of pages14
JournalJournal of Biological Chemistry
Volume292
Issue number1
DOIs
StatePublished - Jan 6 2017

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Caenorhabditis elegans
Copper
Homeostasis
Biochemical Phenomena
Menkes Kinky Hair Syndrome
Membranes
Detoxification
Defects
Hepatolenticular Degeneration
Enterocytes
Poisons

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

The intestinal copper exporter CUA-1 is required for systemic copper homeostasis in Caenorhabditis elegans. / Chun, Haarin; Sharma, Anuj Kumar; Lee, Jaekwon; Chan, Jefferson; Jia, Shang; Kim, Byung Eun.

In: Journal of Biological Chemistry, Vol. 292, No. 1, 06.01.2017, p. 1-14.

Research output: Contribution to journalArticle

Chun, Haarin ; Sharma, Anuj Kumar ; Lee, Jaekwon ; Chan, Jefferson ; Jia, Shang ; Kim, Byung Eun. / The intestinal copper exporter CUA-1 is required for systemic copper homeostasis in Caenorhabditis elegans. In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 1. pp. 1-14.
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