loading page

The CCAAT-binding complex mediates azole susceptibility of Aspergillus fumigatus by suppressing SrbA expression and cleavage
  • +3
  • Chi Zhang,
  • Lu Gao,
  • Yiran Ren,
  • Huiyu Gu,
  • Yuanwei Zhang,
  • Ling Lu
Chi Zhang
Nanjing Normal University College of Life Sciences
Author Profile
Lu Gao
Nanjing Normal University College of Life Sciences
Author Profile
Yiran Ren
Nanjing Normal University College of Life Sciences
Author Profile
Huiyu Gu
Nanjing Normal University College of Life Sciences
Author Profile
Yuanwei Zhang
Nanjing Normal University College of Life Sciences
Author Profile
Ling Lu
Nanjing Normal University College of Life Sciences
Author Profile

Abstract

In fungal pathogens, the transcription factor SrbA (a sterol regulatory element-binding protein, SREBP) and CBC (CCAAT binding complex) have been reported to regulate azole resistance by competitively binding the TR34 region (34 mer) in the promoter of the drug target gene, erg11A. However, current knowledge about how the SrbA and CBC coordinately mediate erg11A expression remains limited. In this study, we uncovered a novel relationship between HapB (a subunit of CBC) and SrbA in which deletion of hapB 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 to erg11A promoter region but also to affect SrbA expression, cleavage, and translocation to nuclei for the function, which ultimately regulate Erg11A expression and azole resistance.

Peer review status:Published

31 Jul 2021Submitted to MicrobiologyOpen
02 Aug 2021Submission Checks Completed
02 Aug 2021Assigned to Editor
04 Aug 2021Reviewer(s) Assigned
09 Sep 2021Review(s) Completed, Editorial Evaluation Pending
09 Sep 2021Editorial Decision: Revise Minor
18 Sep 20211st Revision Received
20 Sep 2021Assigned to Editor
20 Sep 2021Submission Checks Completed
20 Sep 2021Review(s) Completed, Editorial Evaluation Pending
20 Sep 2021Reviewer(s) Assigned
18 Oct 2021Editorial Decision: Revise Minor
20 Oct 20212nd Revision Received
20 Oct 2021Assigned to Editor
20 Oct 2021Submission Checks Completed
20 Oct 2021Review(s) Completed, Editorial Evaluation Pending
20 Oct 2021Editorial Decision: Accept
Nov 2021Published in MicrobiologyOpen volume 10 issue 6. 10.1002/mbo3.1249