Thioredoxin Regulates Multiple Hydrogen Peroxide-Induced Signaling Pathways in Candida albicans

Abstract

The ability of the major systemic fungal pathogen of humans, Candida albicans, to sense and respond to reactive oxygen species (ROS), such as H₂O₂ generated by the host immune system, is required for survival in the host. However, the intracellular signaling mechanisms underlying such responses are poorly understood. Here, we show that thioredoxin (Trx1), in addition to its antioxidant activity, plays a central role in coordinating the response of C. albicans to ROS by regulating multiple pathways. In particular, Trx1 function is important for H₂O₂-induced phosphorylation of the Hog1 stress-activated protein kinase and to reverse H₂O₂-induced oxidation and activation of the AP-1 like transcription factor Cap1. Furthermore, Trx1 regulates H₂O₂-induced hyperpolarized bud growth in a mechanism that involves activation of the Rad53 checkpoint kinase. Consistent with its key roles in responses to ROS, cells lacking Trx1 displayed significantly attenuated virulence in a murine model of C. albicans systemic infection. Collectively, our data indicate that Trx1 has a multifaceted role in H₂O₂ signaling and promotes C. albicans survival in the host.

We thank Al Brown, Ken Haynes, Frank Odds, and Elizabeth Veal for helpful discussions and comments on the manuscript. We are also very grateful to Elizabeth Veal (Newcastle University, United Kingdom), and Yue Wang (Institute of Molecular and Cell Biology, Singapore) for reagents.

This work was funded by the Wellcome Trust (J.Q., B.A.M., L.P.E., and D.M.M.), a BBSRC DTG studentship (M.J.P.), and an ORS award from Newcastle University and a Ph.D. studentship from ICAMB (A.D.S.D.).