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Title: The Fungal Cell Death Regulator czt-1 Is Allelic to acr-3

Abstract

Fungal infections have far-reaching implications that range from severe human disease to a panoply of disruptive agricultural and ecological effects, making it imperative to identify and understand the molecular pathways governing the response to antifungal compounds. In this context, CZT-1 (cell death-activated zinc cluster transcription factor) functions as a master regulator of cell death and drug susceptibility in Neurospora crassa. Here we provide evidence indicating that czt-1 is allelic to acr-3, a previously described locus that we now found to harbor a point mutation in its coding sequence. This nonsynonymous amino acid substitution in a low complexity region of CZT-1/ACR-3 caused a robust gain-of-function that led to reduced sensitivity to acriflavine and staurosporine, and increased expression of the drug efflux pump abc-3. Thus, accumulating evidence shows that CZT-1 is an important broad regulator of the cellular response to various antifungal compounds that appear to share common molecular targets.

Authors:
ORCiD logo [1];  [2];  [3]; ORCiD logo [1]
  1. University of Porto (Portugal)
  2. Kansas State University, Manhattan, KS (United States)
  3. University of California, Berkeley, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE; FCT Portugal; FEDER; National Science Foundation (NSF)
OSTI Identifier:
1628395
Grant/Contract Number:  
AC02-05CH11231; PEst-C/SAU/LA0002/2013; FCOMP-01-0124-FEDER-037277; NORTE-07-0124-FEDER-000003; DBI 0742713
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Fungi
Additional Journal Information:
Journal Volume: 5; Journal Issue: 4; Journal ID: ISSN 2309-608X
Publisher:
MDPI
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; antimicrobial drug resistance; cell death; CZT-1; ABC-3; acriflavine; staurosporine

Citation Formats

Gonçalves, A. Pedro, McCluskey, Kevin, Glass, N. Louise, and Videira, Arnaldo. The Fungal Cell Death Regulator czt-1 Is Allelic to acr-3. United States: N. p., 2019. Web. doi:10.3390/jof5040114.
Gonçalves, A. Pedro, McCluskey, Kevin, Glass, N. Louise, & Videira, Arnaldo. The Fungal Cell Death Regulator czt-1 Is Allelic to acr-3. United States. https://doi.org/10.3390/jof5040114
Gonçalves, A. Pedro, McCluskey, Kevin, Glass, N. Louise, and Videira, Arnaldo. Sun . "The Fungal Cell Death Regulator czt-1 Is Allelic to acr-3". United States. https://doi.org/10.3390/jof5040114. https://www.osti.gov/servlets/purl/1628395.
@article{osti_1628395,
title = {The Fungal Cell Death Regulator czt-1 Is Allelic to acr-3},
author = {Gonçalves, A. Pedro and McCluskey, Kevin and Glass, N. Louise and Videira, Arnaldo},
abstractNote = {Fungal infections have far-reaching implications that range from severe human disease to a panoply of disruptive agricultural and ecological effects, making it imperative to identify and understand the molecular pathways governing the response to antifungal compounds. In this context, CZT-1 (cell death-activated zinc cluster transcription factor) functions as a master regulator of cell death and drug susceptibility in Neurospora crassa. Here we provide evidence indicating that czt-1 is allelic to acr-3, a previously described locus that we now found to harbor a point mutation in its coding sequence. This nonsynonymous amino acid substitution in a low complexity region of CZT-1/ACR-3 caused a robust gain-of-function that led to reduced sensitivity to acriflavine and staurosporine, and increased expression of the drug efflux pump abc-3. Thus, accumulating evidence shows that CZT-1 is an important broad regulator of the cellular response to various antifungal compounds that appear to share common molecular targets.},
doi = {10.3390/jof5040114},
journal = {Journal of Fungi},
number = 4,
volume = 5,
place = {United States},
year = {2019},
month = {12}
}

Works referenced in this record:

Rediscovery by Whole Genome Sequencing: Classical Mutations and Genome Polymorphisms in Neurospora crassa
journal, September 2011

  • McCluskey, Kevin; Wiest, Aric E.; Grigoriev, Igor V.
  • G3: Genes|Genomes|Genetics, Vol. 1, Issue 4
  • DOI: 10.1534/g3.111.000307

The fungal threat to global food security
journal, August 2019


Acriflavin resistance controlled by chromosomal genes in Neurospora
journal, December 1965


Molecular and phenotypic characterization of yeast PDR1 mutants that show hyperactive transcription of various ABC multidrug transporter genes
journal, October 1997

  • Carvajal, E.; van den Hazel, H. B.; Cybularz-Kolaczkowska, A.
  • Molecular and General Genetics MGG, Vol. 256, Issue 4
  • DOI: 10.1007/s004380050584

A quantitative analysis of kinase inhibitor selectivity
journal, January 2008

  • Karaman, Mazen W.; Herrgard, Sanna; Treiber, Daniel K.
  • Nature Biotechnology, Vol. 26, Issue 1
  • DOI: 10.1038/nbt1358

Proflavine/acriflavine derivatives with versatile biological activities
journal, June 2019

  • Sabolova, Danica; Kristian, Pavol; Kozurkova, Mária
  • Journal of Applied Toxicology, Vol. 40, Issue 1
  • DOI: 10.1002/jat.3818

Modulation of fungal sensitivity to staurosporine by targeting proteins identified by transcriptional profiling
journal, December 2011

  • Fernandes, Andreia S.; Pedro Gonçalves, A.; Castro, Ana
  • Fungal Genetics and Biology, Vol. 48, Issue 12
  • DOI: 10.1016/j.fgb.2011.09.004

Food security in 2044: How do we control the fungal threat?
journal, August 2019


A Putative Zn2Cys6 Transcription Factor Is Associated With Isoprothiolane Resistance in Magnaporthe oryzae
journal, October 2018


Molecular cloning of the acr-2 gene which controls acriflavine sensitivity in Neurospora crassa
journal, June 1996

  • Akiyama, Masashi; Nakashima, Hideaki
  • Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression, Vol. 1307, Issue 2
  • DOI: 10.1016/0167-4781(96)00042-5

Gain of Function Mutations in CgPDR1 of Candida glabrata Not Only Mediate Antifungal Resistance but Also Enhance Virulence
journal, January 2009


Coping with Stress and the Emergence of Multidrug Resistance in Fungi
journal, March 2015


Involvement of mitochondrial proteins in calcium signaling and cell death induced by staurosporine in Neurospora crassa
journal, October 2015

  • Gonçalves, A. Pedro; Cordeiro, J. Miguel; Monteiro, João
  • Biochimica et Biophysica Acta (BBA) - Bioenergetics, Vol. 1847, Issue 10
  • DOI: 10.1016/j.bbabio.2015.05.011

DNA sequencing with chain-terminating inhibitors
journal, December 1977

  • Sanger, F.; Nicklen, S.; Coulson, A. R.
  • Proceedings of the National Academy of Sciences, Vol. 74, Issue 12
  • DOI: 10.1073/pnas.74.12.5463

The global problem of antifungal resistance: prevalence, mechanisms, and management
journal, December 2017

  • Perlin, David S.; Rautemaa-Richardson, Riina; Alastruey-Izquierdo, Ana
  • The Lancet Infectious Diseases, Vol. 17, Issue 12
  • DOI: 10.1016/S1473-3099(17)30316-X

Analysis of the DNA sequence of the putative ABC transporter NCU09975 in Neurospora crassa strains carrying acriflavin resistance markers.
journal, January 2012

  • Wiest, Aric E.; Koch, Sarah; McCluskey, Kevin
  • Fungal Genetics Reports, Vol. 59, Issue 1
  • DOI: 10.4148/1941-4765.1012

CZT-1 Is a Novel Transcription Factor Controlling Cell Death and Natural Drug Resistance in Neurospora crassa
journal, April 2014

  • Gonçalves, A. Pedro; Hall, Charles; Kowbel, David J.
  • G3: Genes|Genomes|Genetics, Vol. 4, Issue 6
  • DOI: 10.1534/g3.114.011312

Functional Profiling of Transcription Factor Genes in Neurospora crassa
journal, July 2017

  • Carrillo, Alexander J.; Schacht, Patrick; Cabrera, Ilva E.
  • G3: Genes|Genomes|Genetics, Vol. 7, Issue 9
  • DOI: 10.1534/g3.117.043331

The Global Burden of Fungal Diseases
journal, March 2016

  • Vallabhaneni, Snigdha; Mody, Rajal K.; Walker, Tiffany
  • Infectious Disease Clinics of North America, Vol. 30, Issue 1
  • DOI: 10.1016/j.idc.2015.10.004

Regulated Forms of Cell Death in Fungi
journal, September 2017


The Fungal Genetics Stock Center: a repository for 50 years of fungal genetics research
journal, January 2010


Activation of a TRP-like channel and intracellular Ca2+ dynamics during phospholipase-C-mediated cell death
journal, July 2014

  • Goncalves, A. P.; Cordeiro, J. M.; Monteiro, J.
  • Journal of Cell Science, Vol. 127, Issue 17
  • DOI: 10.1242/jcs.152058

Aminoacridines, potent inhibitors of protein kinase C.
journal, April 1988