HgrA is necessary and sufficient to drive hyphal growth in the dimorphic pathogen Penicillium marneffei

Abstract

SummaryFungi produce multiple morphological forms as part of developmental programs or in response to changing, often stressful, environmental conditions. An opportunistic pathogen of humans, Penicillium marneffei displays multicellular hyphal growth and asexual development (conidiation) in the environment at 25°C and unicellular yeast growth in macrophages at 37°C. We characterized the transcription factor, hgrA, which contains a C2H2 DNA binding domain closely related to that of the stress-response regulators Msn2/4 of Saccharomyces cerevisiae. Northern hybridization analysis demonstrated that hgrA expression is specific to hyphal growth, and its constitutive overexpression prevents conidiation and yeast growth, even in the presence of inductive cues, and causes apical hyperbranching during hyphal growth. Consistent with its expression pattern, deletion of hgrA causes defects in hyphal morphogenesis and the dimorphic transition from yeast cells to hyphae. Specifically, loss of HgrA causes cell wall defects, reduced expression of cell wall biosynthetic enzymes and increased sensitvity to cell wall, oxidative, but not osmotic stress agents. These data suggest that HgrA does not have a direct role in the response to stress but is an inducer of the hyphal growth program and its activity must be downregulated to allow alternative developmental programs, including the morphogenesis of yeast cells in macrophages.

The PaPsr1 and PaWhi2 genes are members of the regulatory network that connect stationary phase to mycelium differentiation and reproduction in Podospora anserina

“…On the contrary, we could not evidence an important function in stress resistance for PaWhi2 and PaPsr1, indicating a lack of conservation of this function. It was previously demonstrated that orthologues of S. cerevisiae MSN2, the transcription factor acting downstream of WHI2 and PSR1 in S. cerevisiae (Kaida et al 2002), may (Dinamarco et al 2012) or may not have crucial role in stress resistance (Bugeja et al 2013;Nicholls et al 2004;Seidl et al 2004), confirming that control of stress resistance by WHI2/PSR1/MSN2 may not be a conserved feature in ascomycetes. Another feature that may not be conserved is the plasma membrane localization of PSR1 (Siniossoglou et al 2000), as PaPsr1 lacks the key residues showed to be involved in membrane binding.…”

Fungal Dimorphism and Virulence: Molecular Mechanisms for Temperature Adaptation, Immune Evasion, and In Vivo Survival

“…This indicates the potential for iron metabolism not regulated by SREB to affect the temperature-dependent morphologic switch [73]. In T. marneffei , conversion to hyphae and maintenance of filamentous morphology at 25°C is governed by transcription factors encoded by HGRA and TUPA , respectively [74, 75]. In addition to transcriptional regulators, N-acetylglucosamine (GlcNAc) accelerates the conversion from yeast to hyphae in B. dermatitidis and H. capsulatum via NGT1 and NGT2 transmembrane transporters [76].…”

Shaping Up for Battle: Morphological Control Mechanisms in Human Fungal Pathogens

“…Do other fungal pathogens possess similar networks to control morphology (and associated virulence attributes) in response to environmental cues such as those encountered in the host? A hypha-specific transcriptional regulator that is both necessary and sufficient to drive hyphal growth as well as inhibit conidiation and yeast growth has recently been identified in P. marneffei [29]. The DRK1 hybrid histidine kinase is also known to function as a global regulator of morphology and virulence in both B. dermatitidis and H. capsulatum [30].…”