Stress-Activated Protein Kinases in Human Fungal Pathogens

Alison M Day,Janet Quinn

doi:10.3389/fcimb.2019.00261

Abstract

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 Saccharomyces cerevisiae. Here, we use this a platform from which to compare SAPK signaling mechanisms in three major fungal pathogens of humans, Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans. 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.

Highlights

Stress responses are essential for pathogenic fungi to survive hostile environments encountered in the host (Brown et al, 2017), and it is apparent that stress-activated protein kinase (SAPK) pathways are central in mediating such responses and virulence in many fungal pathogens
The High Osmolarity Glycerol (HOG) pathway in S. cerevisiae is arguably the best characterized SAPK pathway, and using this as a reference we describe related SAPK pathways in three major fungal pathogens of humans; Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans
This review has highlighted how, in addition to stress resistance, SAPKs co-ordinate a myriad of distinct responses, dependant on the fungal pathogen in question

Summary

INTRODUCTION

Stress responses are essential for pathogenic fungi to survive hostile environments encountered in the host (Brown et al, 2017), and it is apparent that stress-activated protein kinase (SAPK) pathways are central in mediating such responses and virulence in many fungal pathogens. SAPKs were first identified in the model yeast Saccharomyces cerevisiae where the High Osmolarity Glycerol (HOG) pathway was shown to regulate the cellular response to osmotic stress (Brewster et al, 1993). Mammalian homologs, of the yeast Hog SAPK, namely p38 and JNK (cJun N-terminal kinase), were discovered (Galcheva-Gargova et al, 1994; Han et al, 1994). The high level of conservation between mammalian and yeast SAPKs is demonstrated by the fact that human p38 can complement the stress-sensitive phenotypes of the S. cerevisiae hog mutant (Han et al, 1994). The SAPK phosphorylates a range of different nuclear and cytoplasmic substrates triggering a myriad of distinct cellular responses

SAPKs and Fungal Pathogenesis

ASPERGILLUS FUMIGATUS SAKA AND MPKC

CONCLUDING REMARKS