Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
MRC Centre for Medical Mycology at the University of Aberdeen, Aberdeen Fungal Group, Institute of Medical Sciences, Aberdeen, AB25 2ZD, UK.
Sci Rep. 2017 Oct 30;7(1):14340. doi: 10.1038/s41598-017-14756-4.
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.
应激激活蛋白激酶（SAPK）途径是进化上保守的真核信号模块，对人类致病真菌的毒力至关重要。白色念珠菌中的 Hog1 SAPK 对许多宿主施加的应激有强烈的磷酸化反应，对毒力是必需的。目前的定论是，应激诱导的磷酸化激活 SAPK，并促进其核积累，这是 SAPK 依赖的应激保护基因表达所必需的。在这里，我们挑战这个定论。构建了将 Hog1 固定在质膜或组成性核内的白色念珠菌菌株。引人注目的是，将 Hog1 固定在质膜上并没有消除应激抗性或应激诱导的基因表达。此外，防止 Hog1 的核积累对两种不同的系统性感染模型中的白色念珠菌毒力没有影响。然而，将 Hog1 固定在质膜上确实会影响信号保真度，以及 SAPK 的应激诱导磷酸化的幅度和动力学。总之，这些发现挑战了 SAPK 的核积累是 SAPK 依赖的基因表达的先决条件的定论，并揭示了应激诱导的 Hog1 核积累对于主要人类真菌病原体的毒力是可有可无的。
