Abstract
Pneumocystis carinii (Pc) β-glucans are major components of the organism cell wall; yet, the regulation of Pc cell wall genesis and remodeling is not well understood. Ace2 transcription factors, which are present in many fungi, regulate glucanases and other enzymes needed for cell wall remodeling. The cloning and heterologous expression of PcAce2 in ace2Δ Saccharomyces cerevisiae demonstrated that PcAce2 can restore the defective glucanase and endochitinase gene expression of the mutant as well as regulate cell wall β-glucan biosynthetic genes. Furthermore, when a reconstructed yeast system was used, PcAce2 activated the transcription of the Pneumocystis gsc1 β-glucan synthetase, confirming the activity of a Pc transcription factor on a native Pneumocystis promoter and gene for the first time. We further observed that Pneumocystis binding to host extracellular matrix proteins and lung epithelial cells induced the phosphorylation (activation) of the PcAce2 transcription factor. Finally, we present a novel method that confirms the role of PcAce2 in modulating organism virulence using ace2Δ Candida glabrata infection in neutropenic mice. Together, these results indicate that the adherence of Pc to lung matrix proteins and epithelial cells leads to the activation of the Ace2 transcription factor, which regulates cell wall degradation and biosynthesis genes that are required for cell wall remodeling.
Highlights
Ace2 transcription factors regulate fungal cell wall remodeling
Ace2 transcription factors, which are present in many fungi, regulate glucanases and other enzymes needed for cell wall remodeling
These results indicate that the adherence of Pneumocystis carinii (Pc) to lung matrix proteins and epithelial cells leads to the activation of the Ace2 transcription factor, which regulates cell wall degradation and biosynthesis genes that are required for cell wall remodeling
Summary
Ace transcription factors regulate fungal cell wall remodeling. Results: Pneumocystis carinii Ace (PcAce2) is activated by lung matrix proteins and participates in fungal virulence. We present a novel method that confirms the role of PcAce in modulating organism virulence using ace2⌬ Candida glabrata infection in neutropenic mice Together, these results indicate that the adherence of Pc to lung matrix proteins and epithelial cells leads to the activation of the Ace transcription factor, which regulates cell wall degradation and biosynthesis genes that are required for cell wall remodeling. These studies demonstrated that Pneumocystis recognition of lung epithelial cell surfaces or host matrix proteins such as fibronectin or vitronectin, a process termed thigmotropism, lead to enhanced expression and activity of unique signaling kinases including the PcSte MAP kinase and its downstream partner, the cell wall biosynthetic kinase termed PcCbk (8 –10) These proteins have been shown to have roles in both organism proliferation and cell wall remodeling; the downstream mechanisms that are triggered by these kinases as they act on the Pneumocystis life cycle have remained obscure [9, 10]. Our postulate is that PcAce represents a key component of contact-induced cell signaling and life cycle regulation that is induced by Pneumocystis contact with host cellular substrates
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