Current Understanding of HOG-MAPK Pathway in Aspergillus fumigatus

Abstract

Aspergillus fumigatus is an important opportunistic fungal pathogen that causes lethal systemic invasive aspergillosis. It must be able to adapt to stress in the microenvironment during host invasion and systemic spread. The high-osmolarity glycerol (HOG) mitogen-activated protein kinase (MAPK) signaling pathway is a key element that controls adaptation to environmental stress. It plays a critical role in the virulence of several fungal pathogens. In this review, we summarize the current knowledge about the functions of different components of the HOG-MAPK pathway in A. fumigatus through mutant analysis or inferences from the genome annotation, focusing on their roles in adaptation to stress, regulation of infection-related morphogenesis, and effect on virulence. We also briefly compare the functions of the HOG pathway in A. fumigatus with those in the model fungi Saccharomyces cerevisiae and Aspergillus nidulans as well as several other human and plant pathogens including Candida albicans, Cryptococcus neoformans, and Magnaporthe oryzae. The genes described in this review mainly include tcsB, fos1, skn7, sho1, pbs2, and sakA whose deletion mutants have already been established in A. fumigatus. Among them, fos1 has been considered a virulence factor in A. fumigatus, indicating that components of the HOG pathway may be suitable as targets for developing new fungicides. However, quite a few of the genes of this pathway, such as sskA (ssk1), sskB, steC, and downstream regulator genes, are not well characterized. System biology approaches may contribute to a more comprehensive understanding of HOG pathway functions with dynamic details.

Functional Analysis of atfA Gene to Stress Response in Pathogenic Thermal Dimorphic Fungus Penicillium marneffei

“…In A. fumigatus , two Hog1 orthologues, SakA and MpkC participate in response to oxidative and nutritional stresses, respectively [32]. In addition, A. fumigatus sakA also shares a conserved role in osmotic stress response as in S. cerevisiae such that A. fumigatus sakA controls the transcription of protein DprB required for osmotic and pH stress [33]. This indicates that overcompensation of P. marneffei atfA mutant strain to osmotic stress might come from the activation of the stress signaling pathway or transcription factor other than SakA-AtfA pathway.…”

Phosphorylation of Aspergillus fumigatus PkaR impacts growth and cell wall integrity through novel mechanisms

“…The prediction of MAP kinase involvement is bolstered by the reported direct phosphorylation of the targeting region of S. cerevisae Bcy1 by MPK1[16], homologous to A. fumigatus MpkA, a key regulator of the cell wall integrity (CWI) pathway [38]. This result thus suggests potential cross talk between the cAMP and CWI pathways, or possibly involvement of the high osmolarity glycerol response pathway, regulated by the MAP kinase SakA [39, 40]. Analysis of the hinge region cluster comprising T121, S122 and S124 produced moderate hits for both calcium/calmodulin-dependent protein kinase (CaM Kinase-II) and glycogen synthase kinase (GKS3) at all three sites (though in the case of S122 the strongest prediction was for PKA, as expected).…”

Osmosensing and osmoregulation in unicellular eukaryotes

“…The HOG signaling pathway plays a crucial role in the virulence of several fungal pathogens such as Aspergillus fumigatus and Canida albicans, because it regulates morphogenesis in fungi (Ma and Li 2012). It has been observed that C. albicans virulence diminishes by the inactivation of some elements of diverse stress responses, including Hog1, which has led to the suggestion that its virulence has evolved in parallel with the response to different stress situations (Brown et al 2014).…”

“…Hence, the details of signal transduction under osmotic stress in C. albicans remain unresolved. Although 3 HKs are present in C. albicans, which are needed for hyphal formation and for its complete virulence (Nagahashi et al 1998;Catlett et al 2003;Ma and Li 2012), only CaSLN1 is structurally and functionally similar to SLN1 of S. cerevisiae; however, the null mutation is not lethal (Ma and Li 2012). Similarly, in Aspergillus nidulans the gene tcsB was characterized and is similar in structure and function to SLN1 (Furukawa et al 2002), but as with CaSLN1, it does not appear to be essential in the osmotic stress response (Saito 2001;Furukawa et al 2002).…”

“…Other elements of the osmotic response pathway have been identified in pathogenic fungi, including Pbs2 and Hog1 (which show structural and functional conservation), and a protein called CaYpd1 that complements Ypd1 function in S. cerevisiae mutants (Calera et al 2000). These are also involved in physiological and morphological responses during invasion and under osmotic and oxidative stress (Ma and Li 2012).…”