The Hog1 Mitogen-Activated Protein Kinase Is Essential in the Oxidative Stress Response and Chlamydospore Formation inCandidaalbicans

Abstract

Candida albicans mutants with mutations in mitogen-activated protein (MAP) kinase HOG1 displayed an increased sensitivity to agents producing reactive oxygen species, such as oxidants (menadione, hydrogen peroxide, or potassium superoxide), and UV light. Consistent with this finding, C. albicans Hog1 was activated not only in response to an increase in external osmolarity, as happens with its Saccharomyces cerevisiae homologue, but also in response to hydrogen peroxide. The Hog1-mediated response to oxidative stress was different from that of transcription factor Cap1, the homologue of S. cerevisiae Yap1, as shown by the different sensitivities to oxidants and the kinetics of cell death of cap1⌬, hog1, and hog1 cap1⌬ mutants. Deletion of CAP1 did not influence the level of Hog1 phosphorylation, and deletion of HOG1 did not affect Cap1 nuclear localization. Moreover, we show that the HOG1 gene plays a role in chlamydospore formation, another oxygenrelated morphogenetic event, as demonstrated by the fact that hog1 cells were unable to generate these thickwalled structures in several media through a mechanism different from that of the EFG1 regulator. This is the first demonstration of the role of the Hog1-mediated MAP kinase pathway in resistance to oxidative stress in pathogenic fungi, and it allows us to propose a molecular model for the oxidative stress response in C. albicans.

Oxidative Stress ActivatesFUS1andRLM1Transcription in the YeastSaccharomyces cerevisiaein an Oxidant-dependent Manner

“…This finding is consistent with the results published by Haghnazari and Heyer (2004), whereas another study (Alonco-Monge et al, 2003) failed to observe Hog1 phosphorylation after 10-min treatment with hydrogen peroxide (Singh, 2000). The significant reduction of RLM1 transcription in hog1⌬ mutants implicates the involvement of Hog1 in RLM1 reporter activation by hydrogen peroxide.…”

Mutant alleles of the essential 14-3-3 gene in Candida albicans distinguish between growth and filamentation

“…This phenotype is very similar to that described for the efg1/efg1 and phosphorylation EFG1(T206A) mutants (Sonneborn et al, 1999). Other pathways and genes have been implicated in chlamydospore formation, including the Hog1 oxidative stress response and alkaline pH response pathways (Alonso-Monge et al, 2003;Nobile et al, 2003). Indeed, the filament phenotype in some of our BMH1 mutants is very similar to that of alkaline pH response regulator mutants: mds3/mds3 and rim101/rim101 deletion strains (Nobile et al, 2003).…”

The MAP kinase Mkc1p is activated under different stress conditions in Candida albicans

“…Hog1p has a significant influence on virulence, as hog1 mutants are almost completely avirulent (Alonso-Monge et al, 1999). Recent findings show that the HOG signalling pathway is responsible for responding to oxidants in C. albicans by phosphorylating Hog1p (Alonso-Monge et al, 2003). There are some other cloned elements of the putative HOG pathway in C. albicans that are homologous to those of S. cerevisiae, such as HK1, NIK1 and SLN1 (encoding two-component protein-kinase membrane receptors) (Calera et al, 1998;Nagahashi et al, 1998;Srikantha et al, 1998), YPD1 and SSK1 (encoding two-component protein kinases) (Calera et al, 2000;Calera & Calderone, 1999), and the MAP kinase kinase PBS2 (Arana et al, 2005).…”