Joan Tilburn

Imperial College London

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Herbert N. Arst

Imperial College London

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Miguel Á. Peñalva

Centro de Investigaciones Biológicas Margarita Salas

Eduardo A. Espeso

Centro de Investigaciones Biológicas Margarita Salas

Steven H. Denison

Eckerd College

Elaine Bignell

University of Exeter

Eliecer Dı́ez

Centro de Investigaciones Biológicas Margarita Salas

Susana Negrete‐Urtasun

Imperial College London

Lynne Rainbow

Imperial College London

América Hervás‐Aguilar

Centro de Investigaciones Biológicas Margarita Salas

Tatiana Múnera‐Huertas

St George's, University of London

Cooperative Institutions

Centro de Investigaciones Biológicas Margarita Salas

Imperial College London

Consejo Superior de Investigaciones Científicas

Royal Victoria Hospital

University of Ulster

London Postgraduate Medical and Dental Education

Hammersmith Hospital

Technische Universität Berlin

University of Essex

Université Paris-Sud

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Ambient pH signal transduction in Aspergillus: completion of gene characterization

Molecular Microbiology (1999)

Susana Negrete‐Urtasun Wolfgang Reiter Eliecer Dı́ez Steven H. Denison Joan Tilburn

This article was published in Mol Microbiol (1999) 33(5): 994–1003. In Fig. 5, lanes 6–10, the growth pH used was neutral, not alkaline as labelled. The text on p. 996 describes the growth pH correctly as neutral. The authors apologize for this error.

Transduction (biophysics)

10.1046/j.1365-2958.1999.01693.x

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Citations (0)

YPXL/I Is a Protein Interaction Motif Recognized by Aspergillus PalA and Its Human Homologue, AIP1/Alix

Molecular and Cellular Biology (2003)

Olivier Vincent Lynne Rainbow Joan Tilburn Herbert N. Arst Miguel Á. Peñalva

The zinc finger transcription factor PacC undergoes two-step proteolytic activation in response to alkaline ambient pH. PalA is a component of the fungal ambient pH signal transduction pathway. Its mammalian homologue AIP1/Alix interacts with the apoptosis-linked protein ALG-2. We show that both PalA and AIP1/Alix recognize a protein-protein binding motif that we denote YPXL/I, where Tyr, Pro, and Leu/Ile are crucial for its interactive properties. Two such motifs flanking the signaling protease cleavage site mediate direct binding of PalA to PacC, required for the first and only pH-regulated cleavage of this transcription factor. PalA can bind the "closed" (i.e., wild-type full-length) conformer of PacC, suggesting that PalA binding constitutes the first stage in the two-step proteolytic cascade, recruiting or facilitating access of the signaling protease, presumably PalB. In addition to recognizing YPXL/I motifs, both PalA and AIP1/Alix interact with the Aspergillus class E Vps protein Vps32 homologue, a member of a protein complex involved in the early steps of the multivesicular body pathway, suggesting that this interaction is an additional feature of proteins of the PalA/AIP1/Alix family.

Cleavage (geology)

10.1128/mcb.23.5.1647-1655.2003

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Citations (156)

Nonsense-Mediated mRNA Decay Mutation in Aspergillus nidulans

Eukaryotic Cell (2006)

Igor Y. Morozov Susana Negrete‐Urtasun Joan Tilburn Christine A. Jansen Mark X. Caddick

An Aspergillus nidulans mutation, designated nmdA1, has been selected as a partial suppressor of a frameshift mutation and shown to truncate the homologue of the Saccharomyces cerevisiae nonsense-mediated mRNA decay (NMD) surveillance component Nmd2p/Upf2p. nmdA1 elevates steady-state levels of premature termination codon-containing transcripts, as demonstrated using mutations in genes encoding xanthine dehydrogenase (hxA), urate oxidase (uaZ), the transcription factor mediating regulation of gene expression by ambient pH (pacC), and a protease involved in pH signal transduction (palB). nmdA1 can also stabilize pre-mRNA (unspliced) and wild-type transcripts of certain genes. Certain premature termination codon-containing transcripts which escape NMD are relatively stable, a feature more in common with certain nonsense codon-containing mammalian transcripts than with those in S. cerevisiae. As in S. cerevisiae, 5' nonsense codons are more effective at triggering NMD than 3' nonsense codons. Unlike the mammalian situation but in common with S. cerevisiae and other lower eukaryotes, A. nidulans is apparently impervious to the position of premature termination codons with respect to the 3' exon-exon junction.

Nonsense mutation

Nonsense-Mediated Decay

Aspergillus nidulans

Stop codon

10.1128/ec.00220-06

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Citations (17)

pH regulation of penicillin production inAspergillus nidulans

FEMS Microbiology Letters (1991)

Ajit J. Shah Joan Tilburn M.W. Adlard Herbert N. Arst

As shown by both bioassay and high-performance liquid chromatographic (HPLC) analysis, penicillin G production by Aspergillus nidulans is subject to regulation by the pH of the growth medium. Penicillin titres were highest at alkaline pH and in strains carrying mutations in the regulatory gene pacC which mimics the effects of growth at alkaline pH. They were lowest at acid pH and in strains carrying mutations in the palA, palB, palC, palE or palF genes which mimic the effects at growth at acid pH.

Aspergillus nidulans

10.1111/j.1574-6968.1991.tb04349.x

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Citations (75)

Activation of theAspergillusPacC zinc finger transcription factor requires two proteolytic steps

The EMBO Journal (2002)

Eliecer Dı́ez Josué Álvaro Eduardo A. Espeso Lynne Rainbow Teresa Suárez

10.1093/emboj/21.6.1350

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Citations (128)

Establishment of the Ambient pH Signaling Complex in Aspergillus nidulans : PalI Assists Plasma Membrane Localization of PalH

Eukaryotic Cell (2007)

Ana M. Calcagno-Pizarelli Susana Negrete‐Urtasun Steven H. Denison Joanna Rudnicka Henk‐Jan Bussink

ABSTRACT The Aspergillus nidulans ambient pH signaling pathway involves two transmembrane domain (TMD)-containing proteins, PalH and PalI. We provide in silico and mutational evidence suggesting that PalI is a three TMD (3-TMD) protein with an N-terminal signal peptide, and we show that PalI localizes to the plasma membrane. PalI is not essential for the proteolytic conversion of the PacC translation product into the processed 27-kDa form, but its absence markedly reduces the accumulation of the 53-kDa intermediate after cells are shifted to an alkaline pH. PalI and its homologues contain a predicted luminal, conserved Gly-Cys-containing motif that distantly resembles a Gly-rich dimerization domain. The Gly44Arg and Gly47Asp substitutions within this motif lead to loss of function. The Gly47Asp substitution prevents plasma membrane localization of PalI-green fluorescent protein (GFP) and leads to its missorting into the multivesicular body pathway. Overexpression of the likely ambient alkaline pH receptor, the 7-TMD protein PalH, partially suppresses the null palI32 mutation. Although some PalH-GFP localizes to the plasma membrane, it predominates in internal membranes. However, the coexpression of PalI to stoichiometrically similar levels results in the strong predominance of PalH-GFP in the plasma membrane. Thus, one role for PalI, but possibly not the only role, is to assist with plasma membrane localization of PalH. These data, considered along with previous reports for both Saccharomyces cerevisiae and A. nidulans , strongly support the prevailing model of pH signaling involving two spatially segregated complexes: a plasma membrane complex containing PalH, PalI, and the arrestin-like protein PalF and an endosomal membrane complex containing PalA and PalB, to which PacC is recruited for its proteolytic activation.

Aspergillus nidulans

10.1128/ec.00275-07

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Citations (87)

Identification, cloning and analysis of the

MGG Molecular & General Genetics (1996)

Andrew MacCabe J. P. T. W. van den Hombergh Joan Tilburn Herbert N. Arst J. Visser

Cloning (programming)

Identification

Human genetics

10.1007/s004380050087

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Citations (2)

Ambient pH signal transduction in Aspergillus: completion of gene characterization

Molecular Microbiology (1999)

Susana Negrete‐Urtasun Wolfgang Reiter Eliecer Dı́ez Steven H. Denison Joan Tilburn

Completing the molecular analysis of the six pal genes of the ambient pH signal transduction pathway in Aspergillus nidulans , we report the characterization of palC and palH . The derived translation product of palH contains 760 amino acids with prediction of seven transmembrane domains in its N‐terminal moiety. Remarkably, a palH frameshift mutant lacking just over half the PalH protein, including almost all of the long hydrophilic region C‐terminal to the transmembrane domains, retains some PalH function. The palC ‐derived translation product contains 507 amino acids, and the null phenotype of a frameshift mutation indicates that at least one of the C‐terminal 142 residues is essential for function. Uniquely among the A. nidulans pH‐signalling pal genes, palC appears to have no Saccharomyces cerevisiae homologue, although it does have a Neurospora crassa expressed sequence tag homologue. In agreement with findings for the palA , palB and palI genes of this signalling pathway, levels of the palC and palH mRNAs do not appear to be pH regulated.

Transduction (biophysics)

10.1046/j.1365-2958.1999.01540.x

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Citations (92)

Activation of the Aspergillus PacC transcription factor in response to alkaline ambient pH requires proteolysis of the carboxy-terminal moiety.

Genes & Development (1995)

Margarita Orejas Eduardo A. Espeso Joan Tilburn Sovan Sarkar Herbert N. Arst

Extremes of pH are an occupational hazard for many microorganisms. In addition to efficient pH homeostasis, survival effectively requires a regulatory system tailoring the syntheses of molecules functioning beyond the cell boundaries (permeases, secreted enzymes, and exported metabolites) to the pH of the growth environment. Our previous work established that the zinc finger PacC transcription factor mediates such pH regulation in the fungus Aspergillus nidulans in response to a signal provided by the products of the six pal genes at alkaline ambient pH. In the presence of this signal, PacC becomes functional, activating transcription of genes expressed at alkaline pH and preventing transcription of genes expressed at acidic pH. Here we detect two forms of PacC in extracts, both forming specific retardation complexes with a PacC-binding site. Under acidic growth conditions or in acidity-mimicking pal mutants (defective in ambient pH signal transduction), the full-length form of PacC predominates. Under alkaline growth conditions or in alkalinity-mimicking pacCc mutants (independent of the ambient pH signal), a proteolysed version containing the amino-terminal approximately 40% of the protein predominates. This specifically cleaved shorter version is clearly functional, both as an activator for alkaline-expressed genes and as a repressor for acid-expressed genes, but the full-length form of PacC must be inactive. Thus, PacC proteolysis is an essential and pH-sensitive step in the regulation of gene expression by ambient pH. Carboxy-terminal truncations, resulting in a gain-of-function (pacCc) phenotype, bypass the requirement for the pal signal transduction pathway for conversion of the full-length to the proteolyzed functional form.

Aspergillus nidulans

Proteolysis

GATA transcription factor

10.1101/gad.9.13.1622

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Citations (206)

Insertional inactivation and cloning of the wA gene of Aspergillus nidulans.

Genetics. (1990)

Joan Tilburn F. Roussel Claudio Scazzocchio

Abstract We describe examples of wA gene inactivation (resulting in white conidiospores) obtained during transformation of Aspergillus nidulans. One wA- transformant was obtained by transformation with a prn+ plasmid of a strain with green conidia (wA+) which was unable to catabolize L-proline (prn-). This transformant contains a very large number of plasmid copies integrated at a single site inseparable from the wA locus. Passage of this transformant through the sexual cycle generated a variety of novel phenotypes for L-proline utilization, the number and frequency of which depended upon the cleistothecium from which the progeny were obtained, suggesting that the altered phenotypes were due to premeiotic events. The most extreme phenotype was severe hypersensitivity to L-proline. Hypersensitive progeny had a much reduced number of integrated plasmid copies enabling us to identify and clone putative prn-wA fusion sequences and subsequently retrieve wA sequences from a wild-type gene library. One of the wild-type clones overlapped the different sites of the insertional mutations in two wA- transformants and complemented the wA3 allele. Sequences within this clone hybridized to a transcript that was developmentally regulated in the wild type and absent in a number of mutants defective in conidiospore development. A reiterated sequence was also found in the region of the wA gene.

Aspergillus nidulans

Insertional mutagenesis

Wild type

10.1093/genetics/126.1.81

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Citations (44)