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Journal article
The SET-domain protein CgSet4 negatively regulates antifungal drug resistance via the ergosterol biosynthesis transcriptional regulator CgUpc2a
JOURNAL OF BIOLOGICAL CHEMISTRY, v 298(10), 102485
Oct 2022
PMID: 36108742
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Invasive fungal infections, which pose a serious threat to human health, are increasingly associated with a high mor-tality rate and elevated health care costs, owing to rising resistance to current antifungals and emergence of multidrug-resistant fungal species. Candida glabrata is the second to fourth common cause of Candida bloodstream infections. Its high propensity to acquire resistance toward two mainstream drugs, azoles (inhibit ergosterol biosynthesis) and echino-candins (target cell wall), in clinical settings, and its inherent low azole susceptibility render antifungal therapy unsuccessful in many cases. Here, we demonstrate a pivotal role for the SET {suppressor of variegation 3 to 9 [Su(var)3-9], enhancer of zeste [E(z)], and trithorax (Trx)} domain-containing protein, CgSet4, in azole and echinocandin resistance via negative regulation of multidrug transporter-encoding and ergosterol biosynthesis (ERG) genes through the master transcriptional factors CgPdr1 and CgUpc2A, respectively. RNA-Seq analysis revealed that C. glabrata responds to caspofungin (CSP; echinocandin antifungal) stress by downregulation and upre-gulation of ERG and cell wall organization genes, respectively. Although CgSet4 acts as a repressor of the ergosterol biosynthesis pathway via CgUPC2A transcriptional down -regulation, the CSP-induced ERG gene repression is not dependent on CgSet4, as CgSet4 showed diminished abun-dance on the CgUPC2A promoter in CSP-treated cells. Furthermore, we show a role for the last three enzymes of the ergosterol biosynthesis pathway, CgErg3, CgErg5, and CgErg4, in antifungal susceptibility and virulence in C. glabrata. Altogether, our results unveil the link between ergosterol biosynthesis and echinocandin resistance and have implica-tions for combination antifungal therapy.
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- Title
- The SET-domain protein CgSet4 negatively regulates antifungal drug resistance via the ergosterol biosynthesis transcriptional regulator CgUpc2a
- Publication Details
- JOURNAL OF BIOLOGICAL CHEMISTRY, v 298(10), 102485
- Publisher
- ELSEVIER; AMSTERDAM
- Grant note
- This work was supported by the Department of Biotechnology/Wellcome Trust India Alliance Senior Fellowship to R. K. (grant no.: IA/S/15/1/501831; www.indiaalliance.org/) and grants from the Department of Biotechnology (grant nos.: BT/PR42015/MED/29/1561/2021 and BT/PR40336/BRB/10/1921/2020; www.dbtindia.gov.in/), and Science and Engineering Research Board, Department of Science and Technology (grant no.: CRG/2021/000530; www.serb.gov.in/), Government of India. M. R. is a recipient of Junior Research Fellowship sponsored by the Department of Biotechnology, Government of India.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Drexel University
- Web of Science ID
- WOS:000875415100003
- Scopus ID
- 2-s2.0-85139596796
- Other Identifier
- 991021861276504721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology