Characterization of a Candida albicans Mutant Defective in All MAPKs Highlights the Major Role of Hog1 in the MAPK Signaling Network

Abstract

The success of Candida albicans as a pathogen relies on its ability to adapt and proliferate in different environmental niches. Pathways regulated by mitogen-activated protein kinases (MAPKs) are involved in sensing environmental conditions and developing an accurate adaptive response. Given the frequent cooperative roles of these routes in cellular functions, we have generated mutants defective in all combinations of the four described MAPKs in C. albicans and characterized its phenotype regarding sensitiveness to specific drugs, morphogenesis and interaction with host immune cells. We demonstrate that all MAPKs are dispensable in this yeast as a mutant defective in Cek1, Cek2, Mkc1 and Hog1 is viable although highly sensitive to oxidative and osmotic stress, displaying a specific pattern of sensitivity to antifungals. By comparing its phenotype with single, double and triple combinations of MAPK-deletion mutants we were able to unveil a Cek1-independent mechanism for Hog1 resistance to Congo red, and confirm the predominant effect of Hog1 on oxidative and osmotic adaptation. The quadruple mutant produces filaments under non-inducing conditions, but is unable to develop chlamydospores. Furthermore, cek1 cek2 mkc1 hog1 cells switch to the opaque state at high frequency, which is blocked by the ectopic expression of HOG1 suggesting a role of this kinase for phenotypic switching.

EGFR and ERK activation resists flavonoid quercetin‑induced anticancer activities in human cervical cancer cells in vitro

“…The signal is transmitted to the nucleus, leading to the phosphorylation of transcription factors in the nucleus, starting the transcription of target genes, and ultimately leading to biological effects, such as cell proliferation and proliferation (36). In total, 4 major MAPKs have been identified: ERK1/2, JNK/stress activated protein kinases, p38 MAPK and ERK5 (37).…”

Mediator Subunit Med15 Regulates Cell Morphology and Mating in Candida lusitaniae

“…For example, the Rho-GTPase-activating protein (RhoGAP) Rgd1, the CDK inhibitor Pho81 and the nitric oxide dioxygenase Yhb1 were found up-regulated in the med15 Δ mutant in C. lusitaniae and were all reported as negative regulators of filamentation in C. albicans [ 60 , 61 , 62 ]. On the other hand, several kinases involved in oxidative stress response and cell wall organization, such as Cmk1 and Cmk2, or cell wall integrity, such as Mkc1, were up-regulated [ 63 , 64 ]. The activation of the cell wall integrity (CWI) pathway via the MAP kinase Mkc1 in response to cell wall stress has been described in C. albicans .…”

Farnesol and phosphorylation of the transcriptional regulator Efg1 affect Candida albicans white-opaque switching rates

“…Likewise, farnesol is known to affect Cek1-, Hog1-, and Chk1-mediated signaling in addition to its effects on the cAMP/PKA pathway [89][90][91]. As such, the intermediate switching effect seen for the combination of farnesol and the T208E phosphomimetic could reflect farnesol's effects on one or more of these other pathways, at least two of which are known to affect white-opaque switching [51,54,56].…”

“…Switching between the two cell types is controlled by a circuit with eight transcriptional regulators connected by interlocking feedback loops, with Efg1 and Wor1 being especially important for the establishment and maintenance of the white and opaque cell types respectively [38][39][40][41][42][43][44][45][46][47][48][49][50]. Switching rates between the two cell types are dependent on numerous signaling pathways, including the cAMP/protein kinase A pathway [23,[51][52][53], the Hog1 pathway [54][55][56], the Cek1 MAP kinase pathway [51,55], and others [51,[57][58][59][60][61][62][63][64][65]. Environmental conditions that trigger these pathways also affect this switch, including elevated temperature and exposure to N-acetylglucosamine (GlcNAc) [12,23,36,66].…”