Adenylyl Cyclase and Protein Kinase A Play Redundant and Distinct Roles in Growth, Differentiation, Antifungal Drug Resistance, and Pathogenicity of Candida auris
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Despite the recently growing concern of pan-resistant Candida auris infection, the pathogenicity of this ascomycetous fungal pathogen and the signaling circuitries governing its resistance to antifungal drugs are largely unknown. Therefore, we analyzed the pathobiological functions of cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway in C. auris , which plays conserved roles in the growth and virulence of fungal pathogens.
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In other fungal species, bicarbonate plays critical roles in energy metabolism and morphogenesis through the cAMP/PKA signaling pathway that converges at the regulator Efg1.
“In other fungal species, bicarbonate plays critical roles in energy metabolism and morphogenesis, as it is acting through the cyclic adenosine monophosphate–dependent protein kinase A (cAMP/PKA) signaling pathway that converges at the regulator Efg1 (refs. 23–25).”
From Candida auris skin tropism and antifungal resistance are mediated by carbonic anhydrase Nce103 (2025) · cites this paper as [23]
The Introduction and the Results section on morphological transition (pages unavailable in our copy) describe cAMP/PKA signaling in fungal growth and morphogenesis and identify Efg1 as a transcription factor involved in filamentation. They do not establish that bicarbonate acts through this pathway, that the pathway converges on Efg1, or that bicarbonate has a role in energy metabolism. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDeletion of CYR1, RAS1 and CDC25 in strain AR387 increases AMB tolerance.
“Deletion of CYR1, RAS1 and CDC25 in strain AR387 increases AMB tolerance23,25 (Extended Data Fig. 3h)”
From Candida auris skin tropism and antifungal resistance are mediated by carbonic anhydrase Nce103 (2025) · cites this paper as [23]
The Results section on antifungal drug resistance (Fig. 5A; page unavailable) reports that deleting CYR1 increased resistance to amphotericin B. But the tested parental strain was B8441, not AR387, and the paper does not report amphotericin B results for RAS1 or CDC25 deletions. (LLM, conf=0.90)
Experimental — accuracy not yet measuredSome genes expressed in C. albicans hyphal phase have no orthologs in C. auris or no significant change of expression in different conditions inducing C. auris filamentation.
“Moreover, some genes expressed in C. albicans hyphal phase have no orthologs in C. auris (e.g., ECE1, HWP1) or no significant change of expression in different conditions inducing C. auris filamentation (e.g., FLO8, EFG1, BRG1, BCR1, EFH1), suggesting distinct pathways between these genotypically distant Candida spp. (20, 37, 47).”
From Ume6-dependent pathways of morphogenesis and biofilm formation in <i>Candida auris</i> (2024) · cites this paper as [47]
In Results, under “The role of the cAMP/PKA signaling pathway in the morphological transition of C. auris” (Fig. 2C; page not provided), EFG1 was unaffected by hydroxyurea in nearly all strains, and FLO8 was not induced in the wild type. The paper does not establish that ECE1 or HWP1 lack C. auris orthologs or report expression results for BRG1, BCR1, or EFH1. It tests one filamentation-inducing condition, hydroxyurea, and reports increased FLO8 expression in several mutant strains, so it does not support the broader claim about no change across different conditions. (LLM, conf=0.87)
Experimental — accuracy not yet measuredUME6 is significantly overexpressed in some in vitro filament-inducing conditions but not in vivo after passage through the mammalian body.
“Regarding C. auris UME6, significant overexpression of this gene was found in some in vitro filament-inducing conditions (e.g., hydroxyurea treatment) but not in vivo after passage through the mammalian body (20, 47).”
From Ume6-dependent pathways of morphogenesis and biofilm formation in <i>Candida auris</i> (2024) · cites this paper as [47]
The Results section on morphological transition reports that hydroxyurea treatment significantly enhanced UME6 expression in wild-type C. auris. The paper mentions filamentous growth after passage through the mammalian body, but does not report UME6 expression after that passage; its murine virulence study does not establish the claimed lack of overexpression in vivo. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe C. auris cAMP/PKA signaling pathway is important for biofilm formation.
“The C. auris cAMP/PKA signaling pathway has been shown to be important for biofilm formation (59, 60).”
From The <i>Candida auris</i> Hog1 MAP kinase is essential for the colonization of murine skin and intradermal persistence (2024) · cites this paper as [59]
No relevant change of expression was observed among genes involved in the cAMP/PKA pathway following Ume6 hyperactivation.
“While Kim et al. demonstrated a key role of the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway in the filamentation of C. auris (47), we observed no relevant change of expression among genes involved in this pathway (CYR1, BCY1, TPK1, TPK2) following Ume6 hyperactivation (File S1).”
From Ume6-dependent pathways of morphogenesis and biofilm formation in <i>Candida auris</i> (2024) · cites this paper as [47]
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- Authors
- Kim, J.-S., Lee, K.-T., Lee, M. H., Cheong, E., & Bahn, Y.-S.
- Affiliations
- Yonsei University (KR)
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
- Corresponding author
- Bahn, Yong-Sun
- Venue
- mBio
- Publisher
- American Society for Microbiology
- Published
- 2021-10-26
- Volume
- 12
- Issue
- 5
- Pages
- e0272921-e0272921
- ISSN
- 2150-7511 (ISSN-L)
- PMC
- PMC8524339
- OpenAlex
- W3207326205
- Cited by
- 53
- References
- 84
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 18 · 2023: 10 · 2022: 2
- FWCI
- 2.37
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mBio (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Ministry of Agriculture, Food and Rural Affairs (916006-2)
- National Research Foundation of Korea (2021R1A2B5B03086596, 2021M3A9I4021434)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Keywords
- Candida auris, adenylate cyclase, protein kinase A, cAMP signaling, antifungal resistance, fungal pathogenicity, fungal virulence, fungal growth, cell differentiation
- MeSH terms
- Candida auris, Cyclic AMP, Adenylyl Cyclases, Animals, Antifungal Agents, Candidiasis, Female, Phenotype, Virulence, Signal Transduction, Gene Expression Regulation, Fungal, Cyclic AMP-Dependent Protein Kinases, Biofilms, Drug Resistance, Fungal, Mice
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