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Review
, 66 (3), 426-46, table of contents

Regulation of Gene Expression by Ambient pH in Filamentous Fungi and Yeasts

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Review

Regulation of Gene Expression by Ambient pH in Filamentous Fungi and Yeasts

Miguel A Peñalva et al. Microbiol Mol Biol Rev.

Abstract

Life, as we know it, is water based. Exposure to hydroxonium and hydroxide ions is constant and ubiquitous, and the evolutionary pressure to respond appropriately to these ions is likely to be intense. Fungi respond to their environments by tailoring their output of activities destined for the cell surface or beyond to the ambient pH. We are beginning to glimpse how they sense ambient pH and transmit this information to the transcription factor, whose roles ensure that a suitable collection of gene products will be made. Although relatively little is known about pH signal transduction itself, its consequences for the cognate transcription factor are much clearer. Intriguingly, homologues of components of this system mediating the regulation of fungal gene expression by ambient pH are to be found in the animal kingdom. The potential applied importance of this regulatory system lies in its key role in fungal pathogenicity of animals and plants and in its control of fungal production of toxins, antibiotics, and secreted enzymes.

Figures

FIG. 1.
FIG. 1.
Formal genetic model of pH regulation in A. nidulans. PacC is synthesized as an inactive form whose activation requires a signal transduced under alkaline pH conditions by the pal signaling pathway. The active form of PacC is a transcriptional repressor of acid-expressed genes, such as pacA and gabA, and a transcriptional activator of alkaline-expressed genes, such as ipnA, prtA, and palD. Mutations inactivating pacC (pacC or pacC+/−) or the pal signaling pathway lead to absence of expression of alkaline genes and derepression of acidic genes, which results in acidity mimicry. Gain-of-function pacCc mutations bypassing the pal signaling pathway (i.e., leading to active PacC at any ambient pH) result in permanent activation of alkaline genes and superrepression of acidic genes, which leads to alkalinity mimicry.
FIG. 2.
FIG. 2.
Schematic representation of PacC and its DNA binding specificity. (A) Functionally relevant regions in PacC are shown, with limits indicated by residue numbers. Interacting regions A, B, and C are required for maintaining the closed PacC conformation (41). The open box denotes the 24-residue signaling protease box (33). The approximate positions of the signaling protease and the processing protease cleavage sites are indicated by arrows. (B) Prediction of specific contacts between residues in the reading α-helix of PacC zinc fingers 2 and 3 and the PacC target hexanucleotide. Experimental evidence and modeling (43) strongly suggest the contacts indicated by the solid lines. Almost every base in both strands of the target site is predicted to establish specific contacts with PacC zinc finger residues. Dotted arrows indicate possible contacts of Asp127 and of Arg153, whose side chain can be modeled as contacting either the phosphate backbone or the O-4 atoms of both the T4′ and T5′ thymines. Note that finger 1 does not appear to be involved in specific contacts with DNA.
FIG. 3.
FIG. 3.
Supershift assay. The full-length, intermediate, and processed PacC-DNA complexes can be resolved in an EMSA gel. The open (intermediate) form has its regions A and B available for interaction with a purified glutathione S-transferase (GST) fusion protein (here GST::PacC[410-678]) containing interacting region C, whereas in full-length, closed PacC these regions are not available (see the schematic representations). The remarkably stable interaction of open PacC with the large (possibly dimeric) GST fusion protein results in markedly reduced mobility (i.e., supershift) of the corresponding protein-DNA complex. The presence or absence from the reaction mixture of the GST::PacC[410-678] fusion protein is indicated by + and −, respectively.
FIG. 4.
FIG. 4.
Current two-step model of PacC proteolytic activation. Details are described in the text. PacC72, PacC53, and PacC27 refer to the 72-kDa full-length, the 53-kDa intermediate, and the 27-kDa processed PacC forms, respectively. The signaling cleavage step requires alkaline pH signaling through the pal pathway and leads to the intermediate, which is committed to the ambient pH-independent processing cleavage step. The processing protease has not yet been identified, but PalB would appear to be the signaling protease recognizing the signaling protease box (shown as an open box). Commitment to processing results from removal of interacting region C, which is also removed by pacCc-truncating mutations. That the signaling cleavage occurs in the cytosol is supported by the nuclear exclusion of its PacC72 substrate and the preferential nuclear localization of its PacC53 product (82). The processing cleavage might be in the cytosol and/or in the nucleus, as indicated by the dotted lines connecting PacC53 and PacC27. pacC is itself an alkali-expressed gene (122).

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