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. CaCl(2)- 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 CaCl(2). 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.
Jia
X M
XM
Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
Wang
Y
Y
Jia
Y
Y
Gao
P H
PH
Xu
Y G
YG
Wang
L
L
Cao
Y Y
YY
Cao
Y B
YB
Zhang
L X
LX
Jiang
Y Y
YY
D000935:Antifungal Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D025141:Drug Resistance, Fungal / Q000235:genetics / Q000502:physiology*; D004875:Ergosterol / Q000096:biosynthesis; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008826:Microbial Sensitivity Tests; D012235:Rhodamines / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D015854:Up-Regulation
D000935:Antifungal Agents; D001393:Azoles; D005656:Fungal Proteins; D008565:Membrane Proteins; D012235:Rhodamines; C026188:rhodamine 6G; D013110:Sphingosine; C005682:safingol; D002118:Calcium; D004875:Ergosterol