RTA2 is involved in calcineurin-mediated azole resistance and sphingoid long-chain base release in Candida albicans

The calcineurin pathway has been reported to be essential for the development of azole resistance in Candida albicans. The depletion or ectopic over-expression of RTA2 increased or decreased susceptibility of C. albicans to azoles, respectively. CaCl₂- induced activation of the calcineurin pathway in wildtype C. albicans promoted resistance to azoles, while the Ca ²⁺ chelator (EGTA), calcineurin inhibitors (FK506 and cyclosporin A) and the deletion of RTA2 blocked the resistance-promoting effects of CaCl₂. Furthermore, we found that RTA2 was up-regulated in a calcineurin-dependent manner. The depletion of RTA2 also made the cell membrane of C. albicans liable to be destroyed by azoles and RTA2 over-expression attenuated the destroying effects. Finally, the disruption of RTA2 caused an increased accumulation of dihydrosphingosine (DHS), one of the two sphingolipid long-chain bases, by decreasing release of DHS. In conclusion, our findings suggest that RTA2 is involved in calcineurin-mediated azole resistance and sphingoid long-chain base release in C. albicans. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Received 14 July 2008; received after revision 29 August 2008; accepted 16 September 2008