The role of heat shock proteins HsfA and Hsp90 and the regulator SmiA at cell wall integrity pathway activity in the opportunistic human pathogen Aspergillus fumigatus

Abstract

The cell wall is essential for the survival of the fungal cell and is also a protective element against environmental stresses preventing osmotic damage to the cell. The underlying mechanisms whereby the fungal cells build and remodel the cell wall under stressing conditions are of great relevance considering the high mortality rates caused by the human opportunistic fungal pathogen Aspergillus fumigatus. Our laboratory has focused on the investigation of the cell wall integrity pathway (CWI), the main signaling transduction pathway responsible for fungal cell wall synthesis. Previously, we identified the physical interaction between the molecular chaperone Hsp90 and different components of the CWI pathway, such as the apical protein kinase PkcA, the terminal MAP kinase MpkA and the main transcription factor of this pathway, RlmA which interaction may be direct or via the Hsp90-MpkA complex. Furthermore, we observed that the loss of function of the transcription factor HsfA, a key regulator of the heat shock response in different organisms, alters the activity of the CWI pathway indicating that there is a direct correlation between cell wall and temperature stresses. Our data also indicate that the CWI pathway in A. fumigatus acts in a coordinated manner alongside other signaling circuits and other regulatory proteins. Among these putative regulators is the SmiA gene, the Saccharomyces cerevisiae homolog SMI1, which is a member of the Pkc1-mediated signaling pathway. Thus, the aims of this project are (i) the identification of HsfA transcriptional targets related to the maintenance of cell wall integrity, (ii) large scale identification of the Hsp90 clientele focusing on proteins that might play a role in the maintenance or reinforcement of cell wall (iii) the molecular characterization of the SmiA gene and (iv) the evaluation of the interaction of SmiA with the CWI pathway components and with Hsp90. (AU)