Conservation in Aspergillus fumigatus of pH-signaling seven transmembrane domain and arrestin proteins, and implications for drug discovery

Section of Microbiology, Faculty of Medicine, Imperial College London, London, UK.
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 12/2012; 1273(1):35-43. DOI: 10.1111/j.1749-6632.2012.06814.x
Source: PubMed


Adaptation to extracellular pH is a major challenge to fungal pathogens that infect mammalian hosts. Among pH responses mounted by diverse fungal pathogens there is a high degree of molecular conservation. This, coupled with the absence of such signaling pathways in mammalian cells, suggests that this crucial fungal survival mechanism might provide a useful means of limiting a broad spectrum of infectious fungal growth. PacC/Rim signaling converts extracellular cues, perceived by the fungal cell at extremes of ambient pH, into a cellular signal moderating the activation and/or derepression of multiple pH-sensitive gene functions including enzymes, permeases, and transporters. Signal transduction via the fungal PacC/Rim pathway involves a seven transmembrane domain (7TMD) receptor-arrestin protein complex. This review will discuss, with particular attention to Aspergillus fumigatus (the major mold pathogen of humans), the conservation of PacC/Rim signal reception proteins, and protein domains, required for tolerance of pH change, and pathogenicity, and the significance of such molecules as targets for interventive therapies.

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    • "Subsequent translocation of the truncated PacC protein, from cytoplasm to nucleus, permits alkaline adaptation via differential expression of genes required to enable growth under alkaline extracellular conditions (Tilburn et al., 1995; Mingot et al., 1999, 2001; Espeso and Arst, 2000; Espeso et al., 2000). In A. fumigatus the amino acid residues crucial for PalH and PalF interaction are conserved, and in split-ubiquitin analyses the proteins enter into close proximity (Bertuzzi and Bignell, 2011; Bignell, 2012). We have also recently demonstrated the requirement for A. fumigatus PalH for murine infection (Bertuzzi et al., in preparation). "
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    ABSTRACT: Aspergillus fumigatus is the most pathogenic species among the Aspergilli, and the major fungal agent of human pulmonary infection. To prosper in diverse ecological niches, Aspergilli have evolved numerous mechanisms for adaptive gene regulation, some of which are also crucial for mammalian infection. Among the molecules which govern such responses, integral membrane receptors are thought to be the most amenable to therapeutic modulation. This is due to the localization of these molecular sensors at the periphery of the fungal cell, and to the prevalence of small molecules and licensed drugs which target receptor-mediated signaling in higher eukaryotic cells. In this review we highlight the progress made in characterizing receptor-mediated environmental adaptation in A. fumigatus and its relevance for pathogenicity in mammals. By presenting a first genomic survey of integral membrane proteins in this organism, we highlight an abundance of putative seven transmembrane domain (7TMD) receptors, the majority of which remain uncharacterized. Given the dependency of A. fumigatus upon stress adaptation for colonization and infection of mammalian hosts, and the merits of targeting receptor-mediated signaling as an antifungal strategy, a closer scrutiny of sensory perception and signal transduction in this organism is warranted.
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    ABSTRACT: Fungi are exposed to broadly fluctuating environmental conditions, to which adaptation is crucial for their survival. An ability to respond to a wide pH range, in particular, allows them to cope with rapid changes in their extracellular settings. PacC/Rim signalling elicits the primary pH response in both model and pathogenic fungi and has been studied in multiple fungal species. In the predominant human pathogenic fungi, namely Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans, this pathway is required for many functions associated with pathogenesis and virulence. Aspects of this pathway are fungus-specific and do not exist in mammalian cells. In this review, we highlight recent advances in our understanding of PacC/Rim-mediated functions and discuss the growing interest in this cascade and its factors as potential drug targets for antifungal strategies. We focus on both conserved and distinctive features in model and pathogenic fungi, highlighting the specificities of PacC/Rim signalling in C. albicans, A. fumigatus and C. neoformans. We consider the role of this pathway in fungal virulence, including modulation of the host immune response. Finally, as now recognized for other signalling cascades, we highlight the role of pH in adaptation to antifungal drug pressure. By acting on the PacC/Rim pathway, it may therefore be possible (i) to ensure fungal specificity and to limit the side effects of drugs, (ii) to ensure broad-spectrum efficacy, (iii) to attenuate fungal virulence, (iv) to obtain additive or synergistic effects with existing antifungal drugs through tolerance inhibition and (v) to slow the emergence of resistant mutants.
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