The CCAAT-binding complex mediates azole susceptibility of Aspergillus fumigatus by suppressing SrbA expression and cleavage.
Antifungal Agents
/ pharmacology
Aspartic Acid Endopeptidases
/ genetics
Aspergillus fumigatus
/ drug effects
Azoles
/ pharmacology
CCAAT-Binding Factor
/ genetics
Cytochrome P450 Family 51
/ genetics
Drug Resistance, Fungal
/ genetics
Fungal Proteins
/ genetics
Gene Expression Regulation, Fungal
Microbial Sensitivity Tests
Mutation
Proteolysis
Sterol Regulatory Element Binding Proteins
/ genetics
Ubiquitin-Protein Ligases
/ genetics
Aspergillus fumigatus
CCAAT-binding complex
SrbA
azole resistance
protein cleavage
Journal
MicrobiologyOpen
ISSN: 2045-8827
Titre abrégé: Microbiologyopen
Pays: England
ID NLM: 101588314
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
revised:
20
10
2021
received:
31
07
2021
accepted:
20
10
2021
entrez:
29
12
2021
pubmed:
30
12
2021
medline:
1
3
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34964293
doi: 10.1002/mbo3.1249
pmc: PMC8608569
doi:
Substances chimiques
Antifungal Agents
0
Azoles
0
CCAAT-Binding Factor
0
Fungal Proteins
0
Sterol Regulatory Element Binding Proteins
0
Cytochrome P450 Family 51
EC 1.14.14.154
Ubiquitin-Protein Ligases
EC 2.3.2.27
Aspartic Acid Endopeptidases
EC 3.4.23.-
signal peptide peptidase
EC 3.4.23.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1249Informations de copyright
© 2021 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.
Références
G3 (Bethesda). 2018 Jul 2;8(7):2291-2299
pubmed: 29739860
Front Microbiol. 2019 Apr 24;10:691
pubmed: 31068906
mSphere. 2016 Mar 02;1(2):
pubmed: 27303716
Appl Environ Microbiol. 1996 Jan;62(1):184-90
pubmed: 16535210
Eukaryot Cell. 2008 May;7(5):747-64
pubmed: 18375617
J Infect Dis. 2017 Aug 15;216(suppl_3):S436-S444
pubmed: 28911045
Nat Commun. 2020 Jan 22;11(1):427
pubmed: 31969561
PLoS Genet. 2011 Dec;7(12):e1002374
pubmed: 22144905
Fungal Genet Biol. 1997 Jun;21(3):373-87
pubmed: 9290250
mBio. 2019 Mar 12;10(2):
pubmed: 30862750
mBio. 2021 Dec 21;12(6):e0300721
pubmed: 34781745
Mol Microbiol. 1996 Apr;20(2):427-34
pubmed: 8733240
Microbiol Mol Biol Rev. 2011 Jun;75(2):213-67
pubmed: 21646428
PLoS One. 2012;7(11):e50034
pubmed: 23226235
PLoS Pathog. 2016 Jul 20;12(7):e1005775
pubmed: 27438727
PLoS Pathog. 2017 Jan 4;13(1):e1006096
pubmed: 28052140
Transpl Infect Dis. 2017 Oct;19(5):
pubmed: 28722255
PLoS Pathog. 2014 Nov 06;10(11):e1004487
pubmed: 25375670
Science. 2015 Mar 27;347(6229):1414-6
pubmed: 25814567
Fungal Genet Biol. 2016 Jan;86:47-57
pubmed: 26701308
Nucleic Acids Res. 2020 Apr 17;48(7):3567-3590
pubmed: 32086516
Nat Commun. 2018 Aug 6;9(1):3098
pubmed: 30082817
Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11041-8
pubmed: 10500120
PLoS Pathog. 2008 Nov;4(11):e1000200
pubmed: 18989462
Cell. 1997 May 2;89(3):331-40
pubmed: 9150132
Appl Microbiol Biotechnol. 2012 Aug;95(4):825-40
pubmed: 22684327
Antimicrob Agents Chemother. 1996 Feb;40(2):279-91
pubmed: 8834867
PLoS Pathog. 2021 Jul 29;17(7):e1009711
pubmed: 34324607
IDrugs. 2008 Sep;11(9):661-70
pubmed: 18763217
Antimicrob Agents Chemother. 2012 Jan;56(1):248-57
pubmed: 22006005
Mol Microbiol. 2016 May;100(4):635-55
pubmed: 26822492
Nutr Rev. 1998 Feb;56(2 Pt 2):S1-3; discussion S54-75
pubmed: 9564170
Infect Immun. 2016 May 24;84(6):1866-1878
pubmed: 27068092
J Mol Biol. 2001 Mar 2;306(4):643-53
pubmed: 11243777
Science. 2018 May 18;360(6390):739-742
pubmed: 29773744
Antimicrob Agents Chemother. 2016 Dec 27;61(1):
pubmed: 27799210
PLoS Genet. 2018 Oct 26;14(10):e1007762
pubmed: 30365497
Appl Microbiol Biotechnol. 2017 May;101(9):3729-3741
pubmed: 28050634
Methods Mol Biol. 2017;1625:249-258
pubmed: 28584995
Eukaryot Cell. 2012 Dec;11(12):1557-67
pubmed: 23104569
Environ Microbiol. 2015 Apr;17(4):994-1008
pubmed: 24612440
J Proteome Res. 2003 Jan-Feb;2(1):89-93
pubmed: 12643547
Antimicrob Agents Chemother. 2021 Mar 18;65(4):
pubmed: 33431412
Biochim Biophys Acta Gene Regul Mech. 2017 May;1860(5):560-570
pubmed: 27939757
PLoS Med. 2008 Nov 11;5(11):e219
pubmed: 18998768
Pharmacology. 2011;88(3-4):213-24
pubmed: 21986253
Antimicrob Agents Chemother. 2007 Jun;51(6):1897-904
pubmed: 17371828