Thioredoxin regulates multiple hydrogen peroxide-induced signaling pathways in Candida albicans.
The ability of the major systemic fungal pathogen of humans, Candida albicans, to sense and respond to reactive oxygen species (ROS), such as H(2)O(2) 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 H(2)O(2)-induced phosphorylation of the Hog1 stress-activated protein kinase and to reverse H(2)O(2)-induced oxidation and activation of the AP-1 like transcription factor Cap1. Furthermore, Trx1 regulates H(2)O(2)-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 H(2)O(2) signaling and promotes C. albicans survival in the host.
da Silva Dantas
Alessandra
A
Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, Tyne and Wear NE2 4HH, United Kingdom.
Patterson
Miranda J
MJ
Smith
Deborah A
DA
Maccallum
Donna M
DM
Erwig
Lars P
LP
Morgan
Brian A
BA
Quinn
Janet
J
D000818:Animals; D015153:Blotting, Western; D002176:Candida albicans / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D002177:Candidiasis / Q000382:microbiology; D002455:Cell Division / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology*; D025301:Hyphae / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D016877:Oxidants / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D014774:Virulence / Q000235:genetics
D005656:Fungal Proteins; D016877:Oxidants; D049452:Green Fluorescent Proteins; D013879:Thioredoxins; D006861:Hydrogen Peroxide; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases