Candida albicans, the major opportunistic fungi of humans, causes life-threatening infections in immuno-compromised individuals such as AIDS patients, organ transplant patients, patients receiving parenteral nutrition, and cancer patients undergoing radiation treatment.Due to limited available therapy options and the emergence of drug resistance, treating fungal infections is challenging.To improve current treatment strategies, we have identified that Rta2p significantly reduced the sensitivity of fluconazole (FLC) to C.albicans modulated by calcium signaling and the expression of RTA2 was under the control of the calcium-activated-calcineurin via its transcriptional factor Crz1 p in C.albicans.In the present study, we found genetically Rta2p was responsible for the reduced effect of calcium on the sensitivity of FLC to C.albicans in a calcineurin dependent manner.The impairment of FLC to the plasma membrane of C.albicans was calcineurin-dependently attenuated by Rta2p.Furthermore, Rta2p was predominantly localized in lipid rafts, but not involved in its formation.Rta2p was required for the localization of 10 proteins to lipid rafts.Of these, 5 proteins (Pma1p, Gas1p homologue, Erg1 1p, Pmt2p and Ali1p) have been reported to be raft-associated and Erg11p is a well-known target of azoles in C.albicans.Rta2p was not involved in virulence.However, genetically compromising the function of Rta2p significantly increased therapeutic efficacy of FLC against C.albicans bloodstream infection.Re-introduction of either one RTA2 allele or the fusion of oestradiol-inducible promoter and ORF of RTA2 significantly reduced FLC efficacy against candidemia.Over-expression of RTA2 induced by oestradiol in vivo also significantly reduced FLC efficacy.The therapeutic potential of the influence of Rta2p on FLC efficacy was further demonstrated by in vivo studies that FLC therapy was significantly more efficacious when the function of Crz1p and Rta2p was alternatively and genetically compromised.In conclusion, our results showed that Rta2p was required for the calcineurin-mediated resistance to FLC and the localization of proteins to lipid rafts in C.albicans.Given that Rta2p governed the therapeutic efficacy of FLC against candidemia, targeting Rta2p has potential for antifungal therapies.