Upc2-mediated mechanisms of azole resistance in Candida auris
Open accessAbstract
Candida auris is an emerging yeast pathogen of major concern because of its ability to cause hospital outbreaks of invasive candidiasis and to develop resistance to antifungal drugs. A majority of C. auris isolates are resistant to fluconazole, an azole drug used for the treatment of invasive candidiasis. Mechanisms of azole resistance are multiple, including mutations in the target gene ERG11 and activation of the transcription factors Tac1b and Mrr1, which control the drug transporters Cdr1 and Mdr1, respectively. We investigated the role of the transcription factor Upc2, which is known to regulate the ergosterol biosynthesis pathway and azole resistance in other Candida spp. Genetic deletion and hyperactivation of Upc2 by epitope tagging in C. auris resulted in drastic increases and decreases in susceptibility to azoles, respectively. This effect was conserved in strains with genetic hyperactivation of Tac1b or Mrr1. Reverse transcription PCR analyses showed that Upc2 regulates ERG11 expression and also activates the Mrr1/Mdr1 pathway. We showed that upregulation of MDR1 by Upc2 could occur independently from Mrr1. The impact of UPC2 deletion on MDR1 expression and azole susceptibility in a hyperactive Mrr1 background was stronger than that of MRR1 deletion in a hyperactive Upc2 background. While Upc2 hyperactivation resulted in a significant increase in the expression of TAC1b , CDR1 expression remained unchanged. Taken together, our results showed that Upc2 is crucial for azole resistance in C. auris , via regulation of the ergosterol biosynthesis pathway and activation of the Mrr1/Mdr1 pathway. Notably, Upc2 is a very potent and direct activator of Mdr1. IMPORTANCE: Candida auris is a yeast of major medical importance causing nosocomial outbreaks of invasive candidiasis. Its ability to develop resistance to antifungal drugs, in particular to azoles (e.g., fluconazole), is concerning. Understanding the mechanisms of azole resistance in C. auris is important and may help in identifying novel antifungal targets. This study shows the key role of the transcription factor Upc2 in azole resistance of C. auris and shows that this effect is mediated via different pathways, including the regulation of ergosterol biosynthesis and also the direct upregulation of the drug transporter Mdr1.
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Addition of a 3 HA tag to the C-terminal domain of zinc cluster transcription factors is efficient for their artificial activation in C. albicans and C. auris.
“The addition of a 3 HA tag to the C-terminal domain of zinc cluster transcription factors was shown to be efficient for their artificial activation in C. albicans and C. auris, presumably by relieving an activation domain from repression by an inhibitory domain (32–35).”
From Ume6-dependent pathways of morphogenesis and biofilm formation in <i>Candida auris</i> (2024) · cites this paper as [32]
The Materials and Methods section describes C-terminal 3xHA tagging as part of a hyperactivation system for zinc cluster transcription factors in C. auris, and the Results report its use for Upc2, Tac1b, and Mrr1. The paper cites earlier work for the method but does not itself establish its effectiveness in C. albicans or explain activation as relief of repression by an inhibitory domain. (LLM, conf=0.85)
Experimental — accuracy not yet measuredUpc2 is integral to azole resistance in Candida auris by facilitating ergosterol biosynthesis and upregulating Mdr1.
“Li et al. identified that Upc2 is integral to azole resistance in Candida auris by facilitating ergosterol biosynthesis and upregulating the expression of the drug transporter Mdr1 [17].”
From Disruption of the UPC2 Gene Enhances Fluconazole Antifungal Activity by Inhibiting HAC1 mRNA Splicing in Candida albicans (2026) · cites this paper as [17]
HA tagging of the Ume6 protein was verified by Western blot using a HA tag monoclonal antibody.
“HA tagging of the Ume6 protein was verified by Western blot using a HA tag monoclonal antibody (Invitrogen, ThermoFisher Scientific, Waltham, MA), as previously described (Fig. S26) (32).”
From Ume6-dependent pathways of morphogenesis and biofilm formation in <i>Candida auris</i> (2024) · cites this paper as [32]
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“Third, it would be important to determine whether inhibiting Upc2 or the UPR pathway is effective against azole-resistant clinical isolates of C. albicans and other pathogenic Candida species such as C. auris , where Upc2 overexpression is frequently associated with drug resistance [17].”
- Authors
- Li, J., Aubry, L., Brandalise, D., Coste, A. T., Sanglard, D., & Lamoth, F.
- Affiliations
- Centre Hospitalier Universitaire Vaudois (CH)
- Department of Laboratory Medicine and Pathology, Institute of Microbiology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
- Venue
- Microbiology Spectrum
- Publisher
- American Society for Microbiology
- Published
- 2024-02-06
- Volume
- 12
- Issue
- 2
- Pages
- e0352623-e0352623
- ISSN
- 2165-0497 (ISSN-L)
- PMC
- PMC10845950
- OpenAlex
- W4390740012
- Cited by
- 33
- References
- 34
- Citations by year
- 2026: 11 · 2025: 13 · 2024: 9
- FWCI
- 11.41
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Microbiology Spectrum (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- SERVAL (Université de Lausanne) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- IRIS (submittedVersion, cc-by)
- Funders
- Swiss National Science Foundation (310030_192611)
- Fondation Santos-Suarez pour la Recherche Médicale
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- Candida auris, azole resistance, fluconazole resistance, MRR1, CDR1, ERG11, ergosterol biosynthesis, transcriptional regulation, invasive candidiasis, antifungal resistance mechanisms
- MeSH terms
- Candida auris, Antifungal Agents, Azoles, Candida albicans, Candidiasis, Ergosterol, Fungal Proteins, Humans, Microbial Sensitivity Tests, Saccharomyces cerevisiae, Transcription Factors, Fluconazole, Drug Resistance, Fungal, Membrane Transport Proteins, Candidiasis, Invasive
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