Faculty of Medicine, Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle Upon Tyne, United Kingdom.
Front Cell Infect Microbiol. 2019 Jul 17;9:261. doi: 10.3389/fcimb.2019.00261. eCollection 2019.
The ability of fungal pathogens to survive hostile environments within the host depends on rapid and robust stress responses. Stress-activated protein kinase (SAPK) pathways are conserved MAPK signaling modules that promote stress adaptation in all eukaryotic cells, including pathogenic fungi. Activation of the SAPK occurs via the dual phosphorylation of conserved threonine and tyrosine residues within a TGY motif located in the catalytic domain. This induces the activation and nuclear accumulation of the kinase and the phosphorylation of diverse substrates, thus eliciting appropriate cellular responses. The Hog1 SAPK has been extensively characterized in the model yeast . Here, we use this a platform from which to compare SAPK signaling mechanisms in three major fungal pathogens of humans, , and . Despite the conservation of SAPK pathways within these pathogenic fungi, evidence is emerging that their role and regulation has significantly diverged. However, consistent with stress adaptation being a common virulence trait, SAPK pathways are important pathogenicity determinants in all these major human pathogens. Thus, the development of drugs which target fungal SAPKs has the exciting potential to generate broad-acting antifungal treatments.
真菌病原体在宿主内生存恶劣环境的能力取决于快速而强大的应激反应。应激激活蛋白激酶 (SAPK) 途径是保守的 MAPK 信号模块，可促进所有真核细胞（包括致病真菌）适应应激。SAPK 的激活是通过位于催化结构域中的 TGY 基序中保守苏氨酸和酪氨酸残基的双重磷酸化来实现的。这会诱导激酶的激活和核积累以及各种底物的磷酸化，从而引发适当的细胞反应。在模型酵母 中，已对 Hog1 SAPK 进行了广泛的研究。在这里，我们使用这个平台来比较人类三大主要真菌病原体 、 和 中的 SAPK 信号机制。尽管这些致病真菌中的 SAPK 途径具有保守性，但有证据表明它们的作用和调节已经显著分化。然而，与应激适应是共同的毒力特征一致，SAPK 途径是所有这些主要人类病原体的重要致病性决定因素。因此，靶向真菌 SAPK 的药物的开发具有产生广泛作用的抗真菌治疗的令人兴奋的潜力。
