Characterization of the APSES-family transcriptional regulators of Histoplasma capsulatum

Longo, Larissa V. G.; Ray, Stephanie C.; Puccia, Rosana; Rappleye, Chad A.

doi:10.1093/femsyr/foy087

Cited by 18 publications

(17 citation statements)

References 53 publications

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“…Notably, a recent publication examining APSES transcription factors in H . capsulatum showed that knockdown of STU1 resulted in a defect in aerial hyphae production [44], which agrees with our data indicating that STU1 is involved in hyphal growth. A number of other putative regulatory factors are members of the MSB2 regulon, and their functions remain to be analyzed.…”

Section: Discussionsupporting

confidence: 91%

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Opposing signaling pathways regulate morphology in response to temperature in the fungal pathogen Histoplasma capsulatum

et al. 2019

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Phenotypic switching between 2 opposing cellular states is a fundamental aspect of biology, and fungi provide facile systems to analyze the interactions between regulons that control this type of switch. A long-standing mystery in fungal pathogens of humans is how thermally dimorphic fungi switch their developmental form in response to temperature. These fungi, including the subject of this study, Histoplasma capsulatum, are temperature-responsive organisms that utilize unknown regulatory pathways to couple their cell shape and associated attributes to the temperature of their environment. H. capsulatum grows as a multicellular hypha in the soil that switches to a pathogenic yeast form in response to the temperature of a mammalian host. These states can be triggered in the laboratory simply by growing the fungus either at room temperature (RT; which promotes hyphal growth) or at 37 °C (which promotes yeast-phase growth). Prior worked revealed that 15% to 20% of transcripts are differentially expressed in response to temperature, but it is unclear which transcripts are linked to specific phenotypic changes, such as cell morphology or virulence. To elucidate temperature-responsive regulons, we previously identified 4 transcription factors (required for yeast-phase growth [Ryp]1–4) that are required for yeast-phase growth at 37 °C; in each ryp mutant, the fungus grows constitutively as hyphae regardless of temperature, and the cells fail to express genes that are normally induced in response to growth at 37 °C. Here, we perform the first genetic screen to identify genes required for hyphal growth of H. capsulatum at RT and find that disruption of the signaling mucin MSB2 results in a yeast-locked phenotype. RNA sequencing (RNAseq) experiments reveal that MSB2 is not required for the majority of gene expression changes that occur when cells are shifted to RT. However, a small subset of temperature-responsive genes is dependent on MSB2 for its expression, thereby implicating these genes in the process of filamentation. Disruption or knockdown of an Msb2-dependent mitogen-activated protein (MAP) kinase (HOG2) and an APSES transcription factor (STU1) prevents hyphal growth at RT, validating that the Msb2 regulon contains genes that control filamentation. Notably, the Msb2 regulon shows conserved hyphal-specific expression in other dimorphic fungi, suggesting that this work defines a small set of genes that are likely to be conserved regulators and effectors of filamentation in multiple fungi. In contrast, a few yeast-specific transcripts, including virulence factors that are normally expressed only at 37 °C, are inappropriately expressed at RT in the msb2 mutant, suggesting that expression of these genes is coupled to growth in the yeast form rather than to temperature. Finally, we find that the yeast-promoting transcription factor Ryp3 associates with the MSB2 promoter and inhibits MSB2 transcript expression at 37 °C, whereas Msb2 inhibits accumulation of Ryp transcripts and proteins at RT. These findings indicate that ...

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Section: Discussionsupporting

confidence: 91%

“…There are 5 APSES transcription factors in H . capsulatum [44], and Stu1 is the only one of the 5 that is transcriptionally induced as yeast cells transition to filaments (Fig 5A). As noted above, msb2 mutant cells fail to induce STU1 (Figs 3C and 5A), but STU1 expression is restored in the complemented strain at RT (Fig 5B).…”

Section: Resultsmentioning

confidence: 99%

Opposing signaling pathways regulate morphology in response to temperature in the fungal pathogen Histoplasma capsulatum

et al. 2019

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“…We reasoned that the H. capsulatum MSB2 regulon was likely to contain regulators and effectors of the hyphal growth program, and indeed confirmed that HOG2 and STU1 are required for filamentation. Notably, a recent publication examining APSES transcription factors in H. capsulatum showed that knockdown of STU1 resulted in a defect in aerial hyphae production [44], which agrees with our data indicating that STU1 is involved in hyphal growth. A number of other putative regulatory factors are members of the MSB2 regulon, and their functions remain to be analyzed.…”

Section: Discussionsupporting

confidence: 93%

“…, has been extensively studied as a developmental regulator [42, 43]. There are five APSES transcription factors in H. capsulatum [44], and Stu1 is the only one of the five that is transcriptionally induced as yeast-cells transition to filaments (Fig. 5A).…”

Section: Resultsmentioning

confidence: 99%

Opposing signaling pathways regulate morphology in response to temperature in the fungal pathogenHistoplasma capsulatum

Rodriguez

Voorhies

Gilmore

et al. 2019

Preprint

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19 20 21 22 23 2 24 25 ABSTRACT26 Phenotypic switching between two opposing cellular states is a fundamental aspect of biology, 27 and fungi provide facile systems to analyze the interactions between regulons that control this 28 type of switch. A long-standing mystery in fungal pathogens of humans is how thermally 29 dimorphic fungi switch their developmental form in response to temperature. These fungi, 30 including the subject of this study, Histoplasma capsulatum, are temperature-responsive 31 organisms that utilize unknown regulatory pathways to couple their cell shape and associated 32 attributes to the temperature of their environment. H. capsulatum grows as a multicellular hypha 33 in the soil that switches to a pathogenic yeast form in response to the temperature of a 34 mammalian host. These states can be triggered in the laboratory simply by growing the fungus 35 either at room temperature (where it grows as hyphae) or at 37ºC (where it grows as yeast). Prior 36 worked revealed that 15-20% of transcripts are differentially expressed in response to 37 temperature, but it is unclear which transcripts are linked to specific phenotypic changes such as 38 cell morphology or virulence. To elucidate temperature-responsive regulons, we previously 39 identified four transcription factors (Ryp1-4) that are required for yeast-phase growth at 37ºC; in 40 each ryp mutant, the fungus grows constitutively as hyphae regardless of temperature and the 41 cells fail to express genes that are normally induced in response to growth at 37ºC. Here we 42 perform the first genetic screen to identify genes required for hyphal growth of H. capsulatum at 43 room temperature and find that disruption of the signaling mucin MSB2 results in a yeast-locked 44 phenotype. RNAseq experiments reveal that MSB2 is not required for the majority of gene 45 expression changes that occur when cells are shifted to room temperature. However, a small 46 subset of temperature-responsive genes is dependent on MSB2 for its expression, thereby 3 47 implicating these genes in the process of filamentation. Disruption or knockdown of an Msb2-48 dependent MAP kinase (HOG2) and an APSES transcription factor (STU1) prevents hyphal 49 growth at room temperature, validating that the Msb2 regulon contains genes that control 50 filamentation. Notably, the Msb2 regulon shows conserved hyphal-specific expression in other 51 dimorphic fungi, suggesting that this work defines a small set of genes that are likely to be 52 conserved regulators and effectors of filamentation in multiple fungi. In contrast, a few yeast-53 specific transcripts, including virulence factors that are normally expressed only at 37ºC, are 54 inappropriately expressed at room temperature in the msb2 mutant, suggesting that expression of 55 these genes is coupled to growth in the yeast form rather than to temperature. Finally, we find 56 that the yeast-promoting transcription factor Ryp3 associates with the MSB2 promoter and 57 inhibits MSB2 transcript expression at 37ºC, whereas Msb2 inhibits...

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“…Taken together, MbsA plays similar roles with RgdA in governing fungal growth, differentiation, secondary metabolism, and virulence may be due to belong to same group (clade A) [ 28 ]. However, MbsA regulates the SakA MAP kinase pathway contrary to RgdA.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the mbsA Gene Encoding a Putative APSES Transcription Factor in Aspergillus fumigatus

Choi

Jun

Lee

et al. 2021

IJMS

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The APSES family proteins are transcription factors (TFs) with a basic helix-loop-helix domain, known to regulate growth, development, secondary metabolism, and other biological processes in Aspergillus species. In the genome of the human opportunistic pathogenic fungus Aspergillus fumigatus, five genes predicted to encode APSES TFs are present. Here, we report the characterization of one of these genes, called mbsA (Afu7g05620). The deletion (Δ) of mbsA resulted in significantly decreased hyphal growth and asexual sporulation (conidiation), and lowered mRNA levels of the key conidiation genes abaA, brlA, and wetA. Moreover, ΔmbsA resulted in reduced spore germination rates, elevated sensitivity toward Nikkomycin Z, and significantly lowered transcripts levels of genes associated with chitin synthesis. The mbsA deletion also resulted in significantly reduced levels of proteins and transcripts of genes associated with the SakA MAP kinase pathway. Importantly, the cell wall hydrophobicity and architecture of the ΔmbsA asexual spores (conidia) were altered, notably lacking the rodlet layer on the surface of the ΔmbsA conidium. Comparative transcriptomic analyses revealed that the ΔmbsA mutant showed higher mRNA levels of gliotoxin (GT) biosynthetic genes, which was corroborated by elevated levels of GT production in the mutant. While the ΔmbsA mutant produced higher amount of GT, ΔmbsA strains showed reduced virulence in the murine model, likely due to the defective spore integrity. In summary, the putative APSES TF MbsA plays a multiple role in governing growth, development, spore wall architecture, GT production, and virulence, which may be associated with the attenuated SakA signaling pathway.

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Characterization of the APSES-family transcriptional regulators of Histoplasma capsulatum

Cited by 18 publications

References 53 publications

Opposing signaling pathways regulate morphology in response to temperature in the fungal pathogen Histoplasma capsulatum

Opposing signaling pathways regulate morphology in response to temperature in the fungal pathogen Histoplasma capsulatum

Opposing signaling pathways regulate morphology in response to temperature in the fungal pathogenHistoplasma capsulatum

Characterization of the mbsA Gene Encoding a Putative APSES Transcription Factor in Aspergillus fumigatus

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