Membrane receptors contribute to activation and efficient signaling of Mitogen-Activated Protein Kinase cascades during adaptation of Aspergillus fumigatus to different stressors and carbon sources

The high osmolarity glycerol (HOG) response pathway is a multifunctional signal transduction pathway that specifically transmits ambient osmotic signals. <i>Saccharomyces cerevisiae</i> Hog1p has two upstream signaling branches, the sensor histidine kinase Sln1p and the receptor Sho1p. The Sho1p branch includes two other proteins, Msb2p mucin and Opy2p. <i>Aspergillus fumigatus </i>is the leading cause of pulmonary fungal diseases. Here, we investigated the roles played by <i>A. fumigatus</i> SlnA^Sln1p,<i> </i>ShoA^Sho1p, MsbA^Msb2p, and OpyA^Opy2p homologues during the activation of the MAPK HOG pathway. The <i>shoA</i>, <i>msbA</i>, and <i>opyA</i> single and double null mutants are important for the cell wall integrity pathway (CWI), oxidative stress and virulence as assessed by a <i>Galleria mellonella</i> model. Genetic interactions of ShoA, MsbA and OpyA are also important for proper activation of the SakA^Hog1p and MpkA^Slt2 cascade and the response to osmotic and cell wall stresses. Comparative label-free quantitative proteomics analysis of the single null mutants with the wild-type strain upon caspofungin exposure indicates that the absence of ShoA, MsbA and OpyA affects the osmotic stress response, carbohydrate metabolism, and protein degradation. The receptor mutants showed altered trehalose and glycogen accumulation suggesting a role for ShoA, MsbA and OpyA in sugar storage. Protein kinase A activity is also decreased in these mutants. We also observed genetic interactions between SlnA, ShoA, MsbA and OpyA, suggesting that both branches are important for activation of the HOG/CWI pathways. Our results help in the understanding of the activation and modulation of the HOG and CWI pathways in this important fungal pathogen.