CHCA-1 is a copper-regulated CTR1 homolog required for normal development, copper accumulation, and copper-sensing behavior in Caenorhabditis elegans

Abstract

Copper plays key roles in catalytic and regulatory biochemical reactions essential for normal growth, development, and health. Dietary copper deficiencies or mutations in copper homeostasis genes can lead to abnormal musculoskeletal development, cognitive disorders, and poor growth. In yeast and mammals, copper is acquired through the activities of the CTR1 family of high-affinity copper transporters. However, the mechanisms of systemic responses to dietary or tissue-specific copper deficiency remain unclear. Here, taking advantage of the animal model <i>Caenorhabditis elegans</i> for studying whole-body copper homeostasis, we investigated the role of a <i>C. elegans</i> CTR1 homolog, CHCA-1, in copper acquisition and in worm growth, development, and behavior. Using sequence homology searches, we identified 10 potential orthologs to mammalian <i>CTR1</i> Among these genes, we found that <i>chca-1</i>, which is transcriptionally up-regulated in the intestine and hypodermis of <i>C. elegans</i> during copper deficiency, is required for normal growth, reproduction, and maintenance of systemic copper balance under copper deprivation. The intestinal copper transporter CUA-1 normally traffics to endosomes to sequester excess copper, and we found here that loss of <i>chca-1</i> caused CUA-1 to mislocalize to the basolateral membrane under copper overload conditions. Moreover, animals lacking <i>chca-1</i> exhibited significantly reduced copper avoidance behavior in response to toxic copper conditions compared with WT worms. These results establish that CHCA-1-mediated copper acquisition in <i>C. elegans</i> is crucial for normal growth, development, and copper-sensing behavior.