Stress-induced nuclear accumulation is dispensable for Hog1-dependent gene expression and virulence in a fungal pathogen

Alison M Day; Carmen M. Herrero-de-Dios; Donna M MacCallum; Alistair J P Brown; Janet Quinn

doi:10.1038/s41598-017-14756-4

Stress-induced nuclear accumulation is dispensable for Hog1-dependent gene expression and virulence in a fungal pathogen

Alison M Day, Carmen M. Herrero-de-Dios, Donna M MacCallum, Alistair J P Brown, Janet Quinn^* (Corresponding Author)

^*Corresponding author for this work

Medical Sciences

Newcastle University

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Abstract

Stress-activated protein kinase (SAPK) pathways are evolutionarily conserved eukaryotic signalling modules that are essential for the virulence of human pathogenic fungi. The Hog1 SAPK in Candida albicans is robustly phosphorylated in response to a number of host-imposed stresses, and is essential for virulence. The current dogma is that stress-induced phosphorylation activates the SAPK, and promotes its nuclear accumulation that is necessary for the expression of SAPK-dependent stress-protective genes. Here we challenge this dogma. C. albicans strains were constructed in which Hog1 was either tethered to the plasma membrane or constitutively nuclear. Strikingly, tethering Hog1 to the plasma membrane did not abrogate stress resistance or stress-induced gene expression. Furthermore, preventing the nuclear accumulation of Hog1 had no impact on C. albicans virulence in two distinct models of systemic infection. However, tethering Hog1 to the plasma membrane did impact on signal fidelity, and on the magnitude and kinetics of the stress-induced phosphorylation of this SAPK. Taken together, these findings challenge the dogma that nuclear accumulation of SAPKs is a pre-requisite for SAPK-dependent gene expression, and reveal that stress-induced nuclear accumulation of Hog1 is dispensable for the virulence of a major human fungal pathogen.

Original language	English
Article number	14340
Number of pages	11
Journal	Scientific Reports
Volume	7
Early online date	30 Oct 2017
DOIs	https://doi.org/10.1038/s41598-017-14756-4
Publication status	Published - 30 Oct 2017

Bibliographical note

The authors thank E. Veal for intellectual input. This work was funded by the UK Biotechnology and Biological Research Council [J.Q. BB/K016393/1; A.J.P.B. BB/K017365/1], the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [D.M.M. NC/N002482/1] and the Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology [097377]). D.M.M. and A.J.P.B. are also supported by the MRC Centre for Medical Mycology at the University of Aberdeen (MR/N006364/1).

Keywords

cellular microbiology
fungal pathogenesis
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Stress-induced nuclear accumulation is dispensable for Hog1-dependent gene expression and virulence in a fungal pathogen
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Donna MacCallum
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Cite this

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abstract = "Stress-activated protein kinase (SAPK) pathways are evolutionarily conserved eukaryotic signalling modules that are essential for the virulence of human pathogenic fungi. The Hog1 SAPK in Candida albicans is robustly phosphorylated in response to a number of host-imposed stresses, and is essential for virulence. The current dogma is that stress-induced phosphorylation activates the SAPK, and promotes its nuclear accumulation that is necessary for the expression of SAPK-dependent stress-protective genes. Here we challenge this dogma. C. albicans strains were constructed in which Hog1 was either tethered to the plasma membrane or constitutively nuclear. Strikingly, tethering Hog1 to the plasma membrane did not abrogate stress resistance or stress-induced gene expression. Furthermore, preventing the nuclear accumulation of Hog1 had no impact on C. albicans virulence in two distinct models of systemic infection. However, tethering Hog1 to the plasma membrane did impact on signal fidelity, and on the magnitude and kinetics of the stress-induced phosphorylation of this SAPK. Taken together, these findings challenge the dogma that nuclear accumulation of SAPKs is a pre-requisite for SAPK-dependent gene expression, and reveal that stress-induced nuclear accumulation of Hog1 is dispensable for the virulence of a major human fungal pathogen.",

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note = "The authors thank E. Veal for intellectual input. This work was funded by the UK Biotechnology and Biological Research Council [J.Q. BB/K016393/1; A.J.P.B. BB/K017365/1], the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [D.M.M. NC/N002482/1] and the Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology [097377]). D.M.M. and A.J.P.B. are also supported by the MRC Centre for Medical Mycology at the University of Aberdeen (MR/N006364/1).",

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AU - Quinn, Janet

N1 - The authors thank E. Veal for intellectual input. This work was funded by the UK Biotechnology and Biological Research Council [J.Q. BB/K016393/1; A.J.P.B. BB/K017365/1], the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [D.M.M. NC/N002482/1] and the Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology [097377]). D.M.M. and A.J.P.B. are also supported by the MRC Centre for Medical Mycology at the University of Aberdeen (MR/N006364/1).

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N2 - Stress-activated protein kinase (SAPK) pathways are evolutionarily conserved eukaryotic signalling modules that are essential for the virulence of human pathogenic fungi. The Hog1 SAPK in Candida albicans is robustly phosphorylated in response to a number of host-imposed stresses, and is essential for virulence. The current dogma is that stress-induced phosphorylation activates the SAPK, and promotes its nuclear accumulation that is necessary for the expression of SAPK-dependent stress-protective genes. Here we challenge this dogma. C. albicans strains were constructed in which Hog1 was either tethered to the plasma membrane or constitutively nuclear. Strikingly, tethering Hog1 to the plasma membrane did not abrogate stress resistance or stress-induced gene expression. Furthermore, preventing the nuclear accumulation of Hog1 had no impact on C. albicans virulence in two distinct models of systemic infection. However, tethering Hog1 to the plasma membrane did impact on signal fidelity, and on the magnitude and kinetics of the stress-induced phosphorylation of this SAPK. Taken together, these findings challenge the dogma that nuclear accumulation of SAPKs is a pre-requisite for SAPK-dependent gene expression, and reveal that stress-induced nuclear accumulation of Hog1 is dispensable for the virulence of a major human fungal pathogen.

AB - Stress-activated protein kinase (SAPK) pathways are evolutionarily conserved eukaryotic signalling modules that are essential for the virulence of human pathogenic fungi. The Hog1 SAPK in Candida albicans is robustly phosphorylated in response to a number of host-imposed stresses, and is essential for virulence. The current dogma is that stress-induced phosphorylation activates the SAPK, and promotes its nuclear accumulation that is necessary for the expression of SAPK-dependent stress-protective genes. Here we challenge this dogma. C. albicans strains were constructed in which Hog1 was either tethered to the plasma membrane or constitutively nuclear. Strikingly, tethering Hog1 to the plasma membrane did not abrogate stress resistance or stress-induced gene expression. Furthermore, preventing the nuclear accumulation of Hog1 had no impact on C. albicans virulence in two distinct models of systemic infection. However, tethering Hog1 to the plasma membrane did impact on signal fidelity, and on the magnitude and kinetics of the stress-induced phosphorylation of this SAPK. Taken together, these findings challenge the dogma that nuclear accumulation of SAPKs is a pre-requisite for SAPK-dependent gene expression, and reveal that stress-induced nuclear accumulation of Hog1 is dispensable for the virulence of a major human fungal pathogen.

KW - cellular microbiology

KW - fungal pathogenesis

KW - transcription

U2 - 10.1038/s41598-017-14756-4

DO - 10.1038/s41598-017-14756-4

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SN - 2045-2322

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JO - Scientific Reports

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M1 - 14340

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Stress-induced nuclear accumulation is dispensable for Hog1-dependent gene expression and virulence in a fungal pathogen

Abstract

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