The <i>Aspergillus</i> pH‐responsive transcription factor PacC regulates virulence

Bignell, Elaine; Negrete-Urtasun, Susana; Calcagno, A. M.; Haynes, Ken; Arst, Herbert N.; Rogers, Thomas R.

doi:10.1111/j.1365-2958.2004.04472.x

Cited by 108 publications

(96 citation statements)

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“…Virulence of A. fumigatus strains was assayed in a murine model for invasive pulmonary aspergillosis described previously (55). Briefly, outbred male mice (strain CD1, 20-28 g; Charles River Laboratories) were used for animal experiments.…”

Section: Methodsmentioning

confidence: 99%

Mevalonate governs interdependency of ergosterol and siderophore biosyntheses in the fungal pathogen Aspergillus fumigatus

Yasmin

Alcàzar-Fuoli

Gründlinger

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Aspergillus fumigatus is the most common airborne fungal pathogen for humans. In this mold, iron starvation induces production of the siderophore triacetylfusarinine C (TAFC). Here we demonstrate a link between TAFC and ergosterol biosynthetic pathways, which are both critical for virulence and treatment of fungal infections. Consistent with mevalonate being a limiting prerequisite for TAFC biosynthesis, we observed increased expression of 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase (Hmg1) under iron starvation, reduced TAFC biosynthesis following lovastatin-mediated Hmg1 inhibition, and increased TAFC biosynthesis following Hmg1 overexpression. We identified enzymes, the acyl-CoA ligase SidI and the enoyl-CoA hydratase SidH, linking biosynthesis of mevalonate and TAFC, deficiency of which under iron starvation impaired TAFC biosynthesis, growth, oxidative stress resistance, and murine virulence. Moreover, inactivation of these enzymes alleviated TAFC-derived biosynthetic demand for mevalonate, as evidenced by increased resistance to lovastatin. Concordant with bilateral demand for mevalonate, iron starvation decreased the ergosterol content and composition, a phenotype that is mitigated in TAFC-lacking mutants.siderophore | isoprenoide | statins

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Section: Methodsmentioning

confidence: 99%

Mevalonate governs interdependency of ergosterol and siderophore biosyntheses in the fungal pathogen Aspergillus fumigatus

Yasmin

Alcàzar-Fuoli

Gründlinger

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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116

127

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“…As a response to zinc deprivation, homologous genes for the transcription factor Zap1 (Eide, 2009;Zhao & Eide, 1997) lead to the process of filamentation in Candida albicans and Aspergillus fumigatus, and have been considered as virulence factors and promising candidates for elucidating the mechanisms of pathogenicity (Bignell et al, 2005;Krappmann et al, 2004;Moreno et al, 2007). In this sense, the presence in our study of a low-affinity zinc ion transporter may indicate, indirectly, the need to eliminate reactive oxygen species through proteins such as cytosolic superoxide dismutase, a copper/zinc-dependent enzyme important for cell detoxification during oxidative metabolism, which is also regarded as a potential virulence factor (Cox et al, 2003;Dias et al, 2006;Narasipura et al, 2003Narasipura et al, , 2005.…”

Section: R Peres Da Silva and Othersmentioning

confidence: 99%

Differential gene expression analysis of Paracoccidioides brasiliensis during keratinocyte infection

Silva

Matsumoto

Braz

et al. 2011

Journal of Medical Microbiology

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Paracoccidioides brasiliensis is the agent of paracoccidioidomycosis, one of the most important systemic fungal diseases in Latin America. This initiates in lung tissue and can subsequently disseminate to other tissues. Clinical manifestations range from localized forms to disseminated disease that can progress to lethality, probably depending on the relationships among the virulence of the fungus, the immune response and the ability to interact with the surface structures and invade epithelial cells and mononuclear cells of the host. It is generally regarded as a multifocal disease, with oral lesions as the prominent feature. The aim of this study was to evaluate P. brasiliensis yeast infection in normal oral keratinocytes (NOKs). The differential expression of mRNAs and proteins was also determined when the fungus was placed in contact with the cell in order to characterize differentially expressed genes and proteins during P. brasiliensis infection. After contact with NOKs, the fungus appeared to induce alterations in the cells, which showed cellular extensions and cavitations, probably resulting from changes in the actin cytoskeleton seen at 5 and 8 h after infection. Levels of protein expression were higher after reisolation of the fungus from infected NOK culture compared with culture of the fungus in medium. The analysis identified transcripts related to 19 proteins involved in different biological processes. Transcripts were found with multiple functions including induction of cytokines, protein metabolism, alternative carbon metabolism, zinc transport and the stress response during contact with NOKs. The proteins found suggested that the yeast was in a stress situation, as indicated by the presence of RDS1. Nevertheless, the yeast seemed to be proliferating and metabolically active, as shown by the presence of a proteasome, short-chain acetylator, glucosamine-6-phosphate isomerase and ADP/ATP carrier transcripts. Additionally, metabolic pathways may have been activated in order to eliminate toxic substances from the cell as a zinc transporter was detected, which is a potential target for the development of future drugs. INTRODUCTIONParacoccidioides brasiliensis is a thermodimorphic pathogenic fungus, the aetiological agent of paracoccidioidomycosis (PCM), an endemic disease geographically limited to Latin America and one of the most prevalent human deep systemic mycoses found in Brazil, Colombia and Venezuela (San-Blas et al., 2002). The transition from mycelium at 25 u C to yeast at 37 u C is essential for P. brasiliensis to establish the disease (Franco et al., 1997). P. brasiliensis may be inhaled and, once in the lungs, the fungus initiates a process of morphological transition into the pathogenic yeast form (San-Blas et al., 2002).PCM has a multiplicity of clinical presentations, from cutaneous to systemic forms, and can attack various tissues, especially the lungs (Benard & Franco, 2007). Oral mucosal lesions are commonly multiple, with a granular, mulberry-like surface and microulcerations, and ...

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“…In C. albicans, this pathway regulates PHR1 and PHR2, encoding two isoforms of the cell-wall glycosidases important for adaptation to ambient pH (Muhlschlegel & Fonzi, 1997), and represses the acid-expressed cell-wall gene RBR1, encoding a glycosylphosphatidylisositol (GPI) protein required for filamentation (Lotz et al, 2004). Finally, defects in ambient pH response lead to reduced virulence in C. albicans, A. nidulans and other pathogenic fungi (Penalva & Arst, 2002;Davis, 2003;Bignell et al, 2005;Cornet et al, 2005;Mitchell et al, 2007;Villar et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Ambient pH signalling in the yeast Yarrowia lipolytica involves YlRim23p/PalC, which interacts with Snf7p/Vps32p, but does not require the long C terminus of YlRim9p/PalI

2008

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A conserved ambient pH signal transduction pathway has been evidenced in both ascomycetous yeasts and filamentous fungi, called the Rim or Pal pathway, respectively. However, closely related PalC orthologues are found only in Yarrowia lipolytica and in filamentous fungi, where the Rim9p/PalI factor has a much longer C-terminal tail than in other yeasts. We show here that, like Aspergillus nidulans palI mutants, a Ylrim9D mutant has a less extreme phenotype than other mutants of the pathway, whereas rim9 mutants in Saccharomyces cerevisiae and Candida albicans reportedly exhibit a tight Rim phenotype. Deletion of the long C-terminal tail of YlRim9p/ PalI had no phenotypic effect on ambient pH signalling. We also show that the Y. lipolytica PalC orthologue, named YlRim23p, is absolutely required for the alkaline pH response. Its only interactant identified in a genome-wide two-hybrid screen is YlSnf7/Vps32p, confirming the link between the Rim and the Vps pathways. YlRim13p and YlRim20p both interact with YlSnf7/ Vps32p but not with YlRim23p. The long C-terminal tail of YlRim9p/PalI interacts neither with YlRim23p nor with YlSnf7/Vps32p. These results show that YlRim23p is a bona fide component of the Rim pathway in Y. lipolytica and that it participates in the complexes linking pH signalling and endocytosis. INTRODUCTIONExtracellular pH regulation plays major roles in the control of many biological processes, including the survival of fungi and bacteria and the virulence of some of these micro-organisms. Environmental pH profoundly affects gene expression in many organisms, especially in those which are able to grow over a wide pH range. Ambient pH-responsive genes include those encoding permeases, plasma-membrane transporters, secreted proteins and enzymes involved in the synthesis of exported metabolites. In the yeast Yarrowia lipolytica, transcription of the XPR2 and AXP1 genes, encoding alkaline and acidic extracellular proteases, respectively, is tightly controlled by a combination of environmental stimuli, including ambient pH and nutrient availability (Ogrydziak et al., 1977;Ogrydziak, 1993). In Candida albicans, the genes encoding the three proteases Sap4p, Sap5p and Sap6p are under the control of extracellular pH, Sap5p being required for E-cadherin degradation during mucosal tissue invasion (Villar et al., 2007). This pathway has been intensively investigated in Aspergillus nidulans (Penalva & Arst, 2002; Herranz et al., 2005;Hervas-Aguilar et al., 2007; Galindo et al., 2007;Penas et al., 2007;Calcagno-Pizarelli et al., 2007), in Y. lipolytica (Lambert et al., 1997; Tréton et al., 2000;Gonzalez-Lopez et al., 2002;Blanchin-Roland et al., 2005), in several other ascomycetes, including Saccharomyces cerevisiae (Li & Mitchell, 1997;Xu & Mitchell, 2001;Vincent et al., 2003;Xu et al., 2004;Boysen & Mitchell, 2006), in C. albicans (Ramon & Fonzi, 2003;Li et al., 2004;Kullas et al., 2004;Cornet et al., 2005;Barwell et al., 2005;Baek et al., 2006), in the basidiomycete Ustilago maydis (Arechiga-Carvajal & Ruiz-...

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The Aspergillus pH‐responsive transcription factor PacC regulates virulence

Cited by 108 publications

References 77 publications

Mevalonate governs interdependency of ergosterol and siderophore biosyntheses in the fungal pathogen Aspergillus fumigatus

Mevalonate governs interdependency of ergosterol and siderophore biosyntheses in the fungal pathogen Aspergillus fumigatus

Differential gene expression analysis of Paracoccidioides brasiliensis during keratinocyte infection

Ambient pH signalling in the yeast Yarrowia lipolytica involves YlRim23p/PalC, which interacts with Snf7p/Vps32p, but does not require the long C terminus of YlRim9p/PalI

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