The Set1 Histone H3K4 Methyltransferase Contributes to Azole Susceptibility in a Species-Specific Manner by Differentially Altering the Expression of Drug Efflux Pumps and the Ergosterol Gene Pathway

Baker, Kortany M; Hoda, Smriti; Saha, Debasmita; Gregor, Justin B; Georgescu, Livia; Serratore, Nina D.; Zhang, Yueping; Cheng, Lizhi; Lanman, Nadia A.; Briggs, Scott

doi:10.1128/aac.02250-21

Cited by 15 publications

(26 citation statements)

References 80 publications

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“…In the human opportunistic pathogen Candida albicans , Set1-mediated H3K4me3 activates mitochondrial protein genes to establish defenses against oxidative stress from host cells during infection [ 18 ]. Set1-mediated H3K4me3 in another opportunistic fungal pathogen Candida glabrata , is necessary for the azole-induced expression of ergosterol biosynthesis genes that mediate drug resistance [ 19 ]. In phytopathogenic fungi, virulence of the wheat and barley pathogen Fusarium graminearum [ 20 ], the rice pathogen Fusarium fujikuroi [ 21 ], the rice blast fungus Magnaporthe oryzae [ 22 ], and the Brassica anthracnose pathogen Colletotrichum higginsianum is positively regulated by H3K4 methylation [ 23 ].…”

Section: Histone Modificationsmentioning

confidence: 99%

Regulatory Roles of Histone Modifications in Filamentous Fungal Pathogens

Lai

Wang

Zheng

et al. 2022

JoF

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Filamentous fungal pathogens have evolved diverse strategies to infect a variety of hosts including plants and insects. The dynamic infection process requires rapid and fine-tuning regulation of fungal gene expression programs in response to the changing host environment and defenses. Therefore, transcriptional reprogramming of fungal pathogens is critical for fungal development and pathogenicity. Histone post-translational modification, one of the main mechanisms of epigenetic regulation, has been shown to play an important role in the regulation of gene expressions, and is involved in, e.g., fungal development, infection-related morphogenesis, environmental stress responses, biosynthesis of secondary metabolites, and pathogenicity. This review highlights recent findings and insights into regulatory mechanisms of histone methylation and acetylation in fungal development and pathogenicity, as well as their roles in modulating pathogenic fungi–host interactions.

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Section: Histone Modificationsmentioning

confidence: 99%

Regulatory Roles of Histone Modifications in Filamentous Fungal Pathogens

Lai

Wang

Zheng

et al. 2022

JoF

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“…Reverse transcription was performed using All-in-One 5X RT MasterMix (ABM, G592). Primer Express 3.0 software was used to design primers and qRT-PCR was performed as previously described (83,84) with at least three biological replicates. Data were analyzed using the comparative C T method (2 -ΔΔ CT ).…”

Section: Methodsmentioning

confidence: 99%

Reduced Cdc14 phosphatase activity impairs septation, hyphal differentiation and pathogenesis and causes echinocandin hypersensitivity inCandida albicans

Milholland

AbdelKhalek

Baker

et al. 2022

Preprint

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The Cdc14 phosphatase family is highly conserved in fungi. In Saccharomyces cerevisiae, Cdc14 is essential for down-regulation of cyclin-dependent kinase activity at mitotic exit. However, this essential function is not broadly conserved and requires a small fraction of normal Cdc14 activity. It remains unclear what fungal Cdc14 functions require high Cdc14 activity. We identified an invariant motif in the disordered C-terminal tail of fungal Cdc14 enzymes that is required for full enzyme activity. Mutation of this motif reduced Cdc14 catalytic rate and provided a tool for studying the biological significance of high Cdc14 activity. A S. cerevisiae strain expressing the reduced-activity hypomorphic mutant allele (cdc14hm) as the sole source of Cdc14 exhibited an unexpected sensitivity to cell wall stresses, including chitin-binding compounds and echinocandin antifungal drugs. Sensitivity to echinocandins was also observed in Schizosaccharomyces pombe and Candida albicans strains lacking CDC14, suggesting this phenotype reflects a conserved function of Cdc14 orthologs in mediating fungal cell wall integrity. In C. albicans, the orthologous cdc14hm allele was sufficient to elicit echinocandin hypersensitivity and perturb cell wall integrity signaling. It also caused striking abnormalities in septum structure and the same cell separation and hyphal differentiation phenotypes previously observed with cdc14 gene deletions. Since hyphal differentiation is important for C. albicans pathogenesis, we assessed the effect of reducing Cdc14 activity on virulence in Galleria mellonella and mouse models of invasive candidiasis. Partial reduction in Cdc14 activity via cdc14hm mutation severely impaired C. albicans virulence in both assays. Our results reveal that high Cdc14 activity promotes fungal cell wall integrity and, in C. albicans, is needed to orchestrate septation and hyphal differentiation, and for pathogenesis. Cdc14 may therefore be worth future exploration as an antifungal drug target.

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“…Candida also develops azole resistance by mutating ERG11 . In a recent report, Set1 mediates the H3K4 histone methylation and loss of SET1 increases susceptibility to azoles by affecting ERG11 expression [ 42 ]. In addition to this, ERG3 mutations results in ergosterol depletion or alternative sterols accumulation and this depends on three stress response regulatory proteins including molecular chaperone Hsp90, protein phosphatase calcineurin, and protein kinase C1 [ 43 ].…”

Section: Mechanism Antifungal Drug Resistancementioning

confidence: 99%

Molecular Mechanisms of Antifungal Resistance in Mucormycosis

Ganesan

Ganapathy

Sekaran

et al. 2022

BioMed Research International

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Mucormycosis is one among the life-threatening fungal infections with high morbidity and mortality. It is an uncommon and rare infection targeting people with altered immunity. This lethal infection induced by fungi belonging to the Mucorales family is very progressive in nature. The incidence has increased in recent decades owing to the rise in immunocompromised patients. Disease management involves a multimodal strategy including early administration of drugs and surgical removal of infected tissues. Among the antifungals, azoles and amphotericin B remain the gold standard drugs of choice for initial treatment. The order Mucorales are developing a high level of resistance to the available systemic antifungal drugs, and the efficacy still remains below par. Deciphering the molecular mechanisms behind the antifungal resistance in Mucormycosis would add vital information to our available antifungal armamentarium and design novel therapies. Therefore, in this review, we have discussed the mechanisms behind Mucormycosis antifungal resistance. Moreover, this review also highlights the basic mechanisms of action of antifungal drugs and the resistance landscape which is expected to augment future treatment strategies.

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The Set1 Histone H3K4 Methyltransferase Contributes to Azole Susceptibility in a Species-Specific Manner by Differentially Altering the Expression of Drug Efflux Pumps and the Ergosterol Gene Pathway

Cited by 15 publications

References 80 publications

Regulatory Roles of Histone Modifications in Filamentous Fungal Pathogens

Regulatory Roles of Histone Modifications in Filamentous Fungal Pathogens

Reduced Cdc14 phosphatase activity impairs septation, hyphal differentiation and pathogenesis and causes echinocandin hypersensitivity inCandida albicans

Molecular Mechanisms of Antifungal Resistance in Mucormycosis

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