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Calcineurin-dependent dephosphorylation of the transcription factor CrzA at specific sites controls conidiation, stress tolerance, and virulence of Aspergillus fumigatus.

Publication ,  Journal Article
Shwab, EK; Juvvadi, PR; Waitt, G; Soderblom, EJ; Barrington, BC; Asfaw, YG; Moseley, MA; Steinbach, WJ
Published in: Mol Microbiol
July 2019

Calcium signaling through calcineurin and its major transcription factor (TF), CrzA, is integral to hyphal growth, stress response and virulence of the pathogenic fungus Aspergillus fumigatus, the leading etiology of invasive aspergillosis. Dephosphorylation of CrzA by calcineurin activates the TF, but the specific phosphorylation sites and their roles in the activation/inactivation mechanism are unknown. Mass spectroscopic analysis identified 20 phosphorylation sites, the majority of which were specific to filamentous fungi and distributed throughout the CrzA protein, with particular concentration in a serine-rich region N-terminal to the conserved DNA-binding domain (DBD). Site-directed mutagenesis of phosphorylated residues revealed that CrzA activity during calcium stimulation can only be suppressed by a high degree of phosphorylation in multiple regions of the protein. Our findings further suggest that this regulation is not solely accomplished through control of CrzA nuclear import. Additionally, we demonstrate the importance of the CrzA phosphorylation state in regulating growth, conidiation, calcium and cell wall stress tolerance, and virulence. Finally, we identify two previously undescribed nuclear localization sequences in the DBD. These findings provide novel insight into the phosphoregulation of CrzA which may be exploited to selectively target A. fumigatus.

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Published In

Mol Microbiol

DOI

EISSN

1365-2958

Publication Date

July 2019

Volume

112

Issue

1

Start / End Page

62 / 80

Location

England

Related Subject Headings

  • Virulence
  • Transcription Factors
  • Stress, Physiological
  • Phosphorylation
  • Mutagenesis, Site-Directed
  • Microbiology
  • Mass Spectrometry
  • Gene Expression Regulation, Fungal
  • Fungal Proteins
  • Cell Wall
 

Citation

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Shwab, E. K., Juvvadi, P. R., Waitt, G., Soderblom, E. J., Barrington, B. C., Asfaw, Y. G., … Steinbach, W. J. (2019). Calcineurin-dependent dephosphorylation of the transcription factor CrzA at specific sites controls conidiation, stress tolerance, and virulence of Aspergillus fumigatus. Mol Microbiol, 112(1), 62–80. https://doi.org/10.1111/mmi.14254
Shwab, E Keats, Praveen R. Juvvadi, Greg Waitt, Erik J. Soderblom, Blake C. Barrington, Yohannes G. Asfaw, M Arthur Moseley, and William J. Steinbach. “Calcineurin-dependent dephosphorylation of the transcription factor CrzA at specific sites controls conidiation, stress tolerance, and virulence of Aspergillus fumigatus.Mol Microbiol 112, no. 1 (July 2019): 62–80. https://doi.org/10.1111/mmi.14254.
Shwab EK, Juvvadi PR, Waitt G, Soderblom EJ, Barrington BC, Asfaw YG, et al. Calcineurin-dependent dephosphorylation of the transcription factor CrzA at specific sites controls conidiation, stress tolerance, and virulence of Aspergillus fumigatus. Mol Microbiol. 2019 Jul;112(1):62–80.
Shwab, E. Keats, et al. “Calcineurin-dependent dephosphorylation of the transcription factor CrzA at specific sites controls conidiation, stress tolerance, and virulence of Aspergillus fumigatus.Mol Microbiol, vol. 112, no. 1, July 2019, pp. 62–80. Pubmed, doi:10.1111/mmi.14254.
Shwab EK, Juvvadi PR, Waitt G, Soderblom EJ, Barrington BC, Asfaw YG, Moseley MA, Steinbach WJ. Calcineurin-dependent dephosphorylation of the transcription factor CrzA at specific sites controls conidiation, stress tolerance, and virulence of Aspergillus fumigatus. Mol Microbiol. 2019 Jul;112(1):62–80.
Journal cover image

Published In

Mol Microbiol

DOI

EISSN

1365-2958

Publication Date

July 2019

Volume

112

Issue

1

Start / End Page

62 / 80

Location

England

Related Subject Headings

  • Virulence
  • Transcription Factors
  • Stress, Physiological
  • Phosphorylation
  • Mutagenesis, Site-Directed
  • Microbiology
  • Mass Spectrometry
  • Gene Expression Regulation, Fungal
  • Fungal Proteins
  • Cell Wall