title: Chromosome 5 monosomy of Candida albicans controls susceptibility to various toxic agents, including major antifungals.
abstract: Candida albicans is a prevailing fungal pathogen with a diploid genome that can adapt to environmental stresses by losing or gaining an entire chromosome or a large portion of a chromosome. We have previously found that the loss of one copy of chromosome 5 (Ch5) allows for adaptation to the toxic sugar l-sorbose. l-Sorbose is similar to caspofungin and other antifungals from the echinocandins class, in that it represses synthesis of cell wall glucan in fungi. Here, we extended the study of the phenotypes controlled by Ch5 copy number. We examined 57 strains, either disomic or monosomic for Ch5 and representing five different genetic backgrounds, and found that the monosomy of Ch5 causes elevated levels of chitin and repressed levels of 1,3-β-glucan components of the cell wall, as well as diminished cellular ergosterol. Increased deposition of chitin in the cell wall could be explained, at least partially, by a 2-fold downregulation of CHT2 on the monosomic Ch5 that encodes chitinase and a 1.5-fold upregulation of CHS7 on Ch1 that encodes the protein required for wild-type chitin synthase III activity. Other important outcomes of Ch5 monosomy consist of susceptibility changes to agents representing four major classes of antifungals. Susceptibility to caspofungin increased or decreased and susceptibility to 5-fluorocytosine decreased, whereas susceptibility to fluconazole and amphotericin B increased. Our results suggest that Ch5 monosomy represents an unrecognized C. albicans regulatory strategy that impinges on multiple stress response pathways.
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Yang
authors.forename: Anatoliy
authors.initials: A
authors.lastname: Kravets
authors.forename: Gabor
authors.initials: G
authors.lastname: Bethlendy
authors.forename: Stephen
authors.initials: S
authors.lastname: Welle
authors.forename: Elena
authors.initials: E
authors.lastname: Rustchenko
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics*; D000077336:Caspofungin; D015825:Chromosomes, Fungal / Q000235:genetics*; D054714:Echinocandins / Q000494:pharmacology; D015725:Fluconazole / Q000494:pharmacology; D005437:Flucytosine / Q000494:pharmacology; D055666:Lipopeptides
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D000666:Amphotericin B; D015725:Fluconazole; D005437:Flucytosine; D000077336:Caspofungin
references.citation: Microbiol Mol Biol Rev. 2011 Jun;75(2):213-67
references.pmid: 21646428
references.citation: Methods Enzymol. 2002;350:3-41
references.pmid: 12073320
references.citation: Jpn J Infect Dis. 2010 Sep;63(5):355-7
references.pmid: 20859005
references.citation: FEMS Yeast Res. 2011 Nov;11(7):552-63
references.pmid: 22093682
references.citation: Eukaryot Cell. 2010 Jul;9(7):991-1008
references.pmid: 20495058
references.citation: Drugs. 2002;62(7):1025-40
references.pmid: 11985489
references.citation: Anal Biochem. 1997 Jun 15;249(1):88-93
references.pmid: 9193713
references.citation: Fungal Genet Biol. 2009 Feb;46(2):159-68
references.pmid: 19059493
references.citation: J Bacteriol. 1993 Nov;175(22):7189-99
references.pmid: 8226665
references.citation: FEMS Microbiol Lett. 2003 Sep 12;226(1):159-67
references.pmid: 13129622
references.citation: J Bacteriol. 1965 Oct;90(4):1073-81
references.pmid: 5847797
references.citation: Clin Infect Dis. 2003 Jan 15;36(Suppl 1):S31-41
references.pmid: 12516028
references.citation: Drug Resist Updat. 2007 Jun;10(3):121-30
references.pmid: 17569573
references.citation: Yeast. 1991 Aug-Sep;7(6):589-98
references.pmid: 1722597
references.citation: Med Mycol. 2011 Jul;49(5):467-74
references.pmid: 21108572
references.citation: J Bacteriol. 1990 Mar;172(3):1276-83
references.pmid: 2407719
references.citation: Yeast. 2008 Jun;25(6):433-48
references.pmid: 18509849
references.citation: Proc Natl Acad Sci U S A. 1972 Feb;69(2):313-7
references.pmid: 4258315
references.citation: Eukaryot Cell. 2004 Dec;3(6):1639-52
references.pmid: 15590837
references.citation: Mol Microbiol. 2008 May;68(3):624-41
references.pmid: 18363649
references.citation: Microbiology (Reading). 2005 Aug;151(Pt 8):2623-2636
references.pmid: 16079341
references.citation: J Clin Microbiol. 1999 Oct;37(10):3332-7
references.pmid: 10488201
references.citation: Science. 2006 Jul 21;313(5785):367-70
references.pmid: 16857942
references.citation: Yeast. 2005 Jan 15;22(1):57-70
references.pmid: 15635674
references.citation: Infect Immun. 1996 Aug;64(8):3244-51
references.pmid: 8757860
references.citation: Antimicrob Agents Chemother. 2006 Jun;50(6):2058-63
references.pmid: 16723566
references.citation: PLoS Pathog. 2008 Apr 04;4(4):e1000040
references.pmid: 18389063
references.citation: Yeast. 2004 Jun;21(8):685-702
references.pmid: 15197733
references.citation: Antimicrob Agents Chemother. 2006 Sep;50(9):3160-1
references.pmid: 16940118
references.citation: Mol Microbiol. 2007 Mar;63(5):1399-413
references.pmid: 17302816
references.citation: Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5150-5
references.pmid: 9560244
references.citation: J Cell Biol. 1999 Jun 14;145(6):1153-63
references.pmid: 10366589
references.citation: Antimicrob Agents Chemother. 2003 Sep;47(9):2717-24
references.pmid: 12936965
references.citation: Emerg Infect Dis. 2012 Jan;18(1):86-90
references.pmid: 22257484
references.citation: Antimicrob Agents Chemother. 2012 Jan;56(1):208-17
references.pmid: 21986821
references.citation: Mol Microbiol. 2000 May;36(4):856-65
references.pmid: 10844673
references.citation: J Bacteriol. 1994 Jun;176(11):3231-41
references.pmid: 8195078
references.citation: Genetics. 1999 Oct;153(2):653-64
references.pmid: 10511546
references.citation: Arch Biochem Biophys. 1972 Nov;153(1):403-6
references.pmid: 4568261
references.citation: Mol Microbiol. 2003 Apr;48(1):225-35
references.pmid: 12657057
references.citation: Mol Microbiol. 2004 Jun;52(5):1451-62
references.pmid: 15165246
references.citation: Antimicrob Agents Chemother. 2012 Dec;56(12):6121-31
references.pmid: 22964252
references.citation: Biochim Biophys Acta. 1968 Feb 1;156(1):1-8
references.pmid: 5645744
references.citation: J Med Chem. 2000 Jun 29;43(13):2493-505
references.pmid: 10891108
references.citation: Biochem J. 1990 Mar 1;266(2):475-80
references.pmid: 2180400
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12147-52
references.pmid: 16099828
references.citation: Fungal Genet Biol. 2008 Oct;45(10):1404-14
references.pmid: 18765290
references.citation: PLoS One. 2010 Jun 11;5(6):e10856
references.pmid: 20552010
references.citation: Antimicrob Agents Chemother. 2003 Apr;47(4):1207-12
references.pmid: 12654648
references.citation: Mol Gen Genet. 1971;111(2):185-93
references.pmid: 5564468
references.citation: FEMS Yeast Res. 2007 Jan;7(1):2-11
references.pmid: 17311580
references.citation: Genetics. 2012 Feb;190(2):537-47
references.pmid: 22135347
references.citation: FEMS Yeast Res. 2010 Mar;10(2):168-76
references.pmid: 20070376
references.citation: Microbiology (Reading). 2002 Apr;148(Pt 4):1061-1072
references.pmid: 11932451
references.citation: Microbiology (Reading). 2010 Nov;156(Pt 11):3432-3444
references.pmid: 20688824
references.citation: J Bacteriol. 1991 Oct;173(20):6586-96
references.pmid: 1917880
references.citation: Antimicrob Agents Chemother. 2004 Jun;48(6):2223-7
references.pmid: 15155225
references.citation: Yeast. 2005 Sep;22(12):957-69
references.pmid: 16134116