UvrY is required for the full virulence of .

is an emerging human pathogen which causes fast and severe infections worldwide. Under the gradual pressure of lacking useful antibiotics, finding a new strategy against infection is urgent. To understand its pathogenesis, we created an AAK1 mini-Tn10 transposon library to study the mechanism of infection. By using a model, we established a screening platform for the purpose of identifying attenuated mutants. The mutant, which conferred the most attenuated toxicity toward , was identified. The mutant was also less virulent in C2C12 fibroblast and mice models, in line with results. To further elucidate the mechanism of UvrY in controlling the toxicity in , we conducted a transcriptomic analysis. The RNAseq results showed that the expression of a unique hemolysin and other virulence factors were regulated by UvrY. Complementation of Ahh1, one of the most important virulence factors, rescued the pore-formation phenotype of mutant in ; however, complementation of endogenous promoter-driven could not produce Ahh1 and rescue the virulence in the mutant. These findings suggest that UvrY is required for the expression of Ahh1 in . Taken together, our results suggested that UvrY controls several different virulence factors and is required for the full virulence of . The two-component regulator UvrY therefore a potential therapeutic target which is worthy of further study.