The CCAAT ‐binding complex mediates azole susceptibility of Aspergillus fumigatus by suppressing SrbA expression and cleavage

In this study, we found that loss of HapB (a subunit of CBC) causes the upregulation of SrbA and SrbA cleavage-related proteins: RbdB, SppA, and the Dsc complex. This facilitates SrbA cleavage and prolongs the nuclear retention of SrbA to further upregulate expression of Erg11A, suggesting a potential interplay exists between SrbA and CBC. AbstractIn fungal pathogens, the transcription factor SrbA (asterolregulatory element-binding protein, SREBP) and CBC (CCAATbindingcomplex) have been reported to regulate azole resistance by competitively binding the TR34 region (34mer) in the promoter of the drug target gene,erg11A. However, current knowledge about how the SrbA and CBC coordinately mediateerg11A expression remains limited. In this study, we uncovered a novel relationship between HapB (a subunit of CBC) and SrbA in which deletion ofhapB significantly prolongs the nuclear retention of SrbA by increasing its expression and cleavage under azole treatment conditions, thereby enhancing Erg11A expression for drug resistance. Furthermore, we verified that loss of HapB significantly induces the expression of the rhomboid protease RbdB, Dsc ubiquitin E3 ligase complex, and signal peptide peptidase SppA, which are required for the cleavage of SrbA, suggesting that HapB acts as a repressor for these genes which contribute to the activation of SrbA by proteolytic cleavage. Together, our study reveals that CBC functions not only to compete with SrbA for binding toerg11A promoter region ...
Source: MicrobiologyOpen - Category: Microbiology Authors: Tags: ORIGINAL ARTICLE Source Type: research