Retracted: Transcription factor Liv4 is required for growth and pathogenesis of <i>Cryptococcus neoformans</i>

Yi, Jun Koo; Sang, Junjun; Zhao, Jingyu; Gao, Lei; Yang, Yuchao; Yan, Lei; Zhang, Chao; Pan, Weihua; Wang, Guizhen; Liao, Wanqing

doi:10.1093/femsyr/foaa015

“…Bzp2p and Gat5p belong to a conserved zinc finger family containing TFs known as GATA-factors, regulating radiation sensitivity and nitrogen catabolite repression when preferred nitrogen sources are absent or limiting ( 28 ). Liv4p is a conserved MYB-like DNA-binding domain TF, regulating growth and virulence in C. neoformans ( 29 ). Hap2p is a subunit of the evolutionary conserved CCAAT-binding h eme a ctivator p rotein (HAP) complex, a heterotrimeric complex composed of Hap2/3/5 and the transcriptional activation subunit, HapX ( 30 ).…”

Section: Resultsmentioning

confidence: 99%

Coregulation of extracellular vesicle production and fluconazole susceptibility in Cryptococcus neoformans

Rizzo,

Trottier,

Moyrand

et al. 2023

mBio

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Resistance to fluconazole (FLC), the most widely used antifungal drug, is typically achieved by altering the azole drug target and/or drug efflux pumps. Recent reports have suggested a link between vesicular trafficking and antifungal resistance. Here, we identified novel Cryptococcus neoformans regulators of extracellular vesicle (EV) biogenesis that impact FLC resistance. In particular, the transcription factor Hap2 does not affect the expression of the drug target or efflux pumps, yet it impacts the cellular sterol profile. Subinhibitory FLC concentrations also downregulate EV production. Moreover, in vitro spontaneous FLC-resistant colonies showed altered EV production, and the acquisition of FLC resistance was associated with decreased EV production in clinical isolates. Finally, the reversion of FLC resistance was associated with increased EV production. These data suggest a model in which fungal cells can regulate EV production in place of regulating the drug target gene expression as a first line of defense against antifungal assault in this fungal pathogen. IMPORTANCE Extracellular vesicles (EVs) are membrane-enveloped particles that are released by cells into the extracellular space. Fungal EVs can mediate community interactions and biofilm formation, but their functions remain poorly understood. Here, we report the identification of the first regulators of EV production in the major fungal pathogen Cryptococcus neoformans . Surprisingly, we uncover a novel role of EVs in modulating antifungal drug resistance. Disruption of EV production was associated with altered lipid composition and changes in fluconazole susceptibility. Spontaneous azole-resistant mutants were deficient in EV production, while loss of resistance restored initial EV production levels. These findings were recapitulated in C. neoformans clinical isolates, indicating that azole resistance and EV production are coregulated in diverse strains. Our study reveals a new mechanism of drug resistance in which cells adapt to azole stress by modulating EV production.

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“…Error bars show means ± SD.Bzp2p and Gat5p belong to a conserved zinc finger family containing TFs known as GATAfactors, regulating radiation sensitivity and nitrogen catabolite repression (NCR) when preferred nitrogen sources are absent or limiting26 . Liv4p is a conserved MYB-like DNA-binding domain TF regulating growth and virulence in C. neoformans27 . Hap2p is a subunit of the evolutionary conserved CCAAT-binding heme activator protein (HAP) complex, a heterotrimeric complex composed of Hap2/3/5 and the transcriptional activation subunit, HapX28 .…”

mentioning

confidence: 99%

Coregulation of extracellular vesicle production and fluconazole susceptibility inCryptococcus neoformans

Rizzo

¹

,

Trottier

²

,

Moyrand

³

et al. 2023

Preprint

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Resistance to fluconazole (FLC), the most widely used antifungal drug, is typically achieved by altering the azole drug target and/or drug efflux pumps. Recent reports have suggested a link between vesicular trafficking and antifungal resistance. Here, we identified novel Cryptococcus neoformans regulators of extracellular vesicle (EV) biogenesis that impact FLC resistance. In particular, the transcription factor Hap2 does not affect the expression of the drug target or efflux pumps, yet it impacts the cellular sterol profile. Subinhibitory FLC concentrations also downregulate EV production. Moreover, in vitro spontaneous FLC-resistant colonies showed altered EV production, and the acquisition of FLC resistance was associated with decreased EV production in clinical isolates. Finally, the reversion of FLC resistance was associated with increased EV production. These data suggest a model in which fungal cells can regulate EV production before regulating gene expression as a first line of defense against antifungal assault in this fungal pathogen.

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“…Remarkably, MylA is an ortholog of Liv4 in C. neoformans . It has been demonstrated that Cn Liv4 is vital for fungal growth, melanization, normal morphology, and lung infection in a mouse model 54 . Although the phyla of C. neoformans and A. nidulans are different, MylA exhibits similar roles in them, i.e., it is essential for fungal growth and morphology.…”

Section: Discussionmentioning

confidence: 99%

The MYB-like protein MylA contributes to conidiogenesis and conidial germination in Aspergillus nidulans

Son,

Cho,

Park

2024

Commun Biol

2

0

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Myeloblastosis (MYB)-like proteins are a family of highly conserved transcription factors in animals, plants, and fungi and are involved in the regulation of mRNA expression of genes. In this study, we identified and characterized one MYB-like protein in the model organism Aspergillus nidulans. We screened the mRNA levels of genes encoding MYB-like proteins containing two MYB repeats in conidia and found that the mRNA levels of four genes including flbD, cicD, and two uncharacterized genes, were high in conidia. To investigate the roles of two uncharacterized genes, AN4618 and AN10944, deletion mutants for each gene were generated. Our results revealed that AN4618 was required for fungal development. Therefore, we further investigated the role of AN4618, named as mylA, encoding the MYB-like protein containing two MYB repeats. Functional studies revealed that MylA was essential for normal fungal growth and development. Phenotypic and transcriptomic analyses demonstrated that deletion of mylA affected stress tolerance, cell wall integrity, and long-term viability in A. nidulans conidia. In addition, the germination rate of the mylA deletion mutant conidia was decreased compared with that of the wild-type conidia. Overall, this study suggests that MylA is critical for appropriate development, conidial maturation, dormancy, and germination in A. nidulans.

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Retracted: Transcription factor Liv4 is required for growth and pathogenesis of Cryptococcus neoformans

Cited by 3 publications

References 48 publications

Coregulation of extracellular vesicle production and fluconazole susceptibility in Cryptococcus neoformans

Coregulation of extracellular vesicle production and fluconazole susceptibility in Cryptococcus neoformans

Coregulation of extracellular vesicle production and fluconazole susceptibility inCryptococcus neoformans

The MYB-like protein MylA contributes to conidiogenesis and conidial germination in Aspergillus nidulans

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