The CueR-regulated transporters CopA and CusFABC coordinate copper detoxification in .

is a zoonotic pathogen that poses a serious threat to shrimp aquaculture and public health worldwide. Copper (Cu) serves as a catalytic cofactor and structural element in bacteria but is toxic in excess. Herein, we report that the CueR-regulated transporters CopA and CusFABC coordinate Cu detoxification in . Through RNA sequencing, we show that most genes in the CueR and Fur regulons are significantly upregulated during response to external Cu. Quantitative real-time PCR (qRT-PCR) showed that and are strongly induced by Cu. Growth curve analyses and spot dilution assay revealed that CopA and CusFABC protect against Cu-induced bactericidal effects. Inductively coupled plasma-mass spectrometry revealed that CopA and CusFABC are involved in maintaining Cu and Fe homoeostasis. Additionally, CopA promotes resistance to pyrithione. In a competitive-infection assay, the and double mutant, but not the single mutants, was significantly attenuated in colonization of the zebrafish intestine. Lastly, qRT-PCR, RNA sequencing, β-galactosidase activity, and AIDmut-Seq analyses revealed that CueR can bind to the promoters of and , and positively regulate their expression. Collectively, utilizes the CueR-regulated transporters CopA and CusFABC to coordinate Cu detoxification and colonization of the zebrafish intestine.