Identification and Characterization of a Novel Copper-Sensing Receptor in C. elegans

Copper is an essential micronutrient in humans, as it plays critical roles in cellular respiration, antioxidant reactions, and neuropeptide synthesis. Copper acts as a reduction-oxidation (redox) cofactor in enzymes that are involved in these metabolic processes. The redox property of copper is required for its biological functions, but it can also lead to the production of reactive oxygen species (ROS) that cause cytotoxicity. Thus, both systemic and cellular levels of copper must be carefully controlled. Dyshomeostasis of copper causes fatal human diseases if left untreated, e.g., copper deficiency as seen in Menkes Disease (MD) and copper overload caused by Wilson Disease (WD). The underlying pathology of copper-dependent diseases are still unclear. The major reason is that copper plays much more complex biological roles than just being an enzyme co-factor. New studies suggest that copper also functions as a cellular signaling molecule. The role of intracellular copper in signaling is supported by the dynamic nature of cellular pools of copper which can be mobilized in both physiological and pathological conditions. These labile copper pools play significant roles in tumorigenesis, lipid metabolism, immunity, diabetes, and nervous system function. In addition to intracellular copper, the possibility that extracellular copper can trigger intracellular signaling has received little attention. This gap in knowledge stems from the lack of knowing the molecular identity of the sub-cellular apparatus that senses extracellular copper and initiates intracellular signaling. In C. elegans, exposure to high levels of copper results in specific avoidance behaviors that depend on primary cilia in ASH sensory neurons. These data suggest that the copper- sensing apparatus may reside in neuronal cilia, a signaling platform for several sensory pathways. Here, we propose to identify the first copper-sensing receptor in animals using C. elegans. C. elegans has evolutionary conserved molecular machinery in regulating copper homeostasis. C. elegans also responds robustly to copper stimulations. This, together with its short generation time (~3 days) and facile and rich genetic tools, makes C. elegans an ideal system for identifying novel copper-sensing receptors. We did a genetic screen in C. elegans and identified CUSR-1 as a candidate copper-sensing receptor. In the current proposal, we propose to test the hypothesis that CUSR-1 is a bona fide copper-sensing receptor and characterize how CUSR-1 senses and transduces extracellular copper signaling. We will take a multidisciplinary approach combining molecular genetics, behavioral analysis, calcium imaging, FRET/BRET, opto- and chemo-genetics. The proposed work will not only lead to the identification of the first copper-sensing receptor in animals, but also provide insights into how extracellular copper transduces signaling inside the cell through cilia. Project Number: 1P20GM161969-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Xinxing Zhang | Institution: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR, OKLAHOMA CITY, OK | Award Amount: $257,400 | Activity Code: P20 | Study Section: Special Emphasis Panel[ZRG1 MCST-H (40)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11267913