Functional divergence of a global regulatory complex governing fungal filamentation.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101239074 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7404 (Electronic) Linking ISSN: 15537390 NLM ISO Abbreviation: PLoS Genet Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, c2005-

Candida albicans/*genetics ; Fungal Proteins/*genetics ; Nuclear Proteins/*genetics ; Saccharomyces cerevisiae Proteins/*genetics ; Trans-Activators/*genetics; Candida albicans/pathogenicity ; Fungi/genetics ; Fungi/pathogenicity ; Gene Expression Regulation, Fungal ; Humans ; Hyphae/genetics ; Hyphae/pathogenicity ; Morphogenesis/genetics ; Multiprotein Complexes/genetics ; Saccharomyces cerevisiae/genetics ; Transcription Factors/genetics

Morphogenetic transitions are prevalent in the fungal kingdom. For a leading human fungal pathogen, Candida albicans, the capacity to transition between yeast and filaments is key for virulence. For the model yeast Saccharomyces cerevisiae, filamentation enables nutrient acquisition. A recent functional genomic screen in S. cerevisiae identified Mfg1 as a regulator of morphogenesis that acts in complex with Flo8 and Mss11 to mediate transcriptional responses crucial for filamentation. In C. albicans, Mfg1 also interacts physically with Flo8 and Mss11 and is critical for filamentation in response to diverse cues, but the mechanisms through which it regulates morphogenesis remained elusive. Here, we explored the consequences of perturbation of Mfg1, Flo8, and Mss11 on C. albicans morphogenesis, and identified functional divergence of complex members. We observed that C. albicans Mss11 was dispensable for filamentation, and that overexpression of FLO8 caused constitutive filamentation even in the absence of Mfg1. Harnessing transcriptional profiling and chromatin immunoprecipitation coupled to microarray analysis, we identified divergence between transcriptional targets of Flo8 and Mfg1 in C. albicans. We also established that Flo8 and Mfg1 cooperatively bind to promoters of key regulators of filamentation, including TEC1, for which overexpression was sufficient to restore filamentation in the absence of Flo8 or Mfg1. To further explore the circuitry through which Mfg1 regulates morphogenesis, we employed a novel strategy to select for mutations that restore filamentation in the absence of Mfg1. Whole genome sequencing of filamentation-competent mutants revealed chromosome 6 amplification as a conserved adaptive mechanism. A key determinant of the chromosome 6 amplification is FLO8, as deletion of one allele blocked morphogenesis, and chromosome 6 was not amplified in evolved lineages for which FLO8 was re-located to a different chromosome. Thus, this work highlights rewiring of key morphogenetic regulators over evolutionary time and aneuploidy as an adaptive mechanism driving fungal morphogenesis.
Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: L.E.C. is a co-founder and shareholder in Bright Angel Therapeutics, a platform company for development of novel antifungal therapeutics. L.E.C. is a consultant for Boragen, a small-molecule development company focused on leveraging the unique chemical properties of boron chemistry for crop protection and animal health.

Antimicrob Agents Chemother. 2017 Oct 24;61(11):. (PMID: 28807920)
Science. 2006 Jul 21;313(5785):367-70. (PMID: 16857942)
Mol Biol Cell. 2004 Oct;15(10):4490-9. (PMID: 15269278)
Eukaryot Cell. 2003 Oct;2(5):1053-60. (PMID: 14555488)
J Bacteriol. 1994 Feb;176(3):756-63. (PMID: 8300529)
Expert Rev Anti Infect Ther. 2017 Apr;15(4):327-330. (PMID: 28152317)
Trends Microbiol. 2014 Dec;22(12):707-14. (PMID: 25262420)
PLoS One. 2011 Apr 07;6(4):e18394. (PMID: 21512583)
J Bacteriol. 1999 Dec;181(24):7524-30. (PMID: 10601210)
Mol Biol Cell. 1998 Jan;9(1):161-71. (PMID: 9436998)
Microbiol Mol Biol Rev. 2011 Jun;75(2):213-67. (PMID: 21646428)
Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13594-9. (PMID: 23904484)
Antimicrob Agents Chemother. 2016 Nov 21;60(12):7468-7480. (PMID: 27736764)
Proc Natl Acad Sci U S A. 2013 Jul 23;110(30):12367-72. (PMID: 23812752)
J Bacteriol. 1990 Mar;172(3):1276-83. (PMID: 2407719)
J Gen Microbiol. 1989 Feb;135(Pt 2):425-34. (PMID: 2693597)
Mol Biol Cell. 2012 Jul;23(14):2692-701. (PMID: 22621896)
Genome Med. 2014 Nov 20;6(11):100. (PMID: 25505934)
PLoS One. 2010 May 13;5(5):e10629. (PMID: 20498713)
Curr Biol. 2009 Apr 28;19(8):621-9. (PMID: 19327993)
Genetics. 2001 Apr;157(4):1523-30. (PMID: 11290709)
Genetics. 2012 Jan;190(1):23-49. (PMID: 22219507)
Science. 2012 Sep 14;337(6100):1353-6. (PMID: 22984072)
Mol Biol Cell. 2006 Jan;17(1):295-307. (PMID: 16267276)
Electrophoresis. 1999 Dec;20(18):3551-67. (PMID: 10612281)
Mol Microbiol. 2008 May;68(3):624-41. (PMID: 18363649)
Clin Microbiol Rev. 2007 Jan;20(1):133-63. (PMID: 17223626)
Sci Transl Med. 2012 Dec 19;4(165):165rv13. (PMID: 23253612)
J Biol Chem. 2001 Dec 28;276(52):48988-96. (PMID: 11595734)
PLoS Genet. 2016 Oct 27;12(10):e1006405. (PMID: 27788136)
Nat Commun. 2015 Mar 31;6:6741. (PMID: 25824284)
Microbiol Mol Biol Rev. 2003 Sep;67(3):400-28, table of contents. (PMID: 12966142)
Eukaryot Cell. 2013 Feb;12(2):244-53. (PMID: 23223039)
Nat Rev Microbiol. 2017 Feb;15(2):96-108. (PMID: 27867199)
J Proteomics. 2014 Apr 4;100:37-43. (PMID: 24513533)
PLoS Genet. 2018 Apr 27;14(4):e1007319. (PMID: 29702647)
Cell Microbiol. 2010 Mar;12(3):273-82. (PMID: 19919567)
Eukaryot Cell. 2009 Nov;8(11):1780-91. (PMID: 19734367)
J Proteomics. 2016 Oct 21;149:64-68. (PMID: 27132685)
Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13223-8. (PMID: 8917572)
EMBO J. 2001 Sep 3;20(17):4742-52. (PMID: 11532938)
Genetics. 2017 Nov;207(3):1195-1211. (PMID: 28912344)
Proteomics. 2015 Apr;15(8):1432-6. (PMID: 25422071)
Mol Microbiol. 1999 May;32(3):533-46. (PMID: 10320576)
Science. 1994 Dec 9;266(5191):1723-6. (PMID: 7992058)
G3 (Bethesda). 2012 Jan;2(1):131-41. (PMID: 22384390)
Clin Microbiol Rev. 2007 Jan;20(1):115-32. (PMID: 17223625)
Antimicrob Agents Chemother. 2011 Sep;55(9):4436-9. (PMID: 21746947)
Nat Chem Biol. 2007 Sep;3(9):541-8. (PMID: 17710100)
PLoS Genet. 2016 Oct 3;12(10):e1006350. (PMID: 27695031)
Mol Cell Biol. 2002 Jun;22(12):3981-93. (PMID: 12024012)
PLoS Genet. 2014 Dec 04;10(12):e1004824. (PMID: 25474009)
Genetics. 2018 Jul;209(3):725-741. (PMID: 29724862)
Cell. 1992 Mar 20;68(6):1077-90. (PMID: 1547504)
PLoS Genet. 2009 Oct;5(10):e1000705. (PMID: 19876375)
Mol Microbiol. 2001 Dec;42(5):1243-57. (PMID: 11886556)
Mol Cell Proteomics. 2011 Dec;10(12):M111.007690. (PMID: 21876204)
Cell. 2015 Feb 12;160(4):771-784. (PMID: 25679766)
Genetics. 2009 Jul;182(3):799-811. (PMID: 19414562)
Curr Biol. 2012 Mar 20;22(6):461-70. (PMID: 22365851)
PLoS Pathog. 2014 Oct 30;10(10):e1004478. (PMID: 25356907)
Proteomics. 2013 Jan;13(1):22-4. (PMID: 23148064)
Eukaryot Cell. 2010 Apr;9(4):634-44. (PMID: 20097739)
mSphere. 2017 Mar 1;2(2):. (PMID: 28261668)
Microbiol Spectr. 2017 Jul;5(4):. (PMID: 28752816)
Cell Cycle. 2012 Dec 1;11(23):4294-5. (PMID: 23095675)
Nature. 2015 Mar 19;519(7543):349-52. (PMID: 25731168)
Annu Rev Microbiol. 2015;69:71-92. (PMID: 26488273)
Annu Rev Microbiol. 2006;60:69-105. (PMID: 16704346)
Annu Rev Microbiol. 2017 Sep 8;71:753-775. (PMID: 28886681)
Nat Rev Microbiol. 2011 Aug 16;9(10):737-48. (PMID: 21844880)
Infect Immun. 2005 Feb;73(2):1239-42. (PMID: 15664973)
Eukaryot Cell. 2011 Aug;10(8):1004-12. (PMID: 21642508)
PLoS Biol. 2013 Sep;11(9):e1001653. (PMID: 24058295)
G3 (Bethesda). 2017 Nov 6;7(11):3797-3808. (PMID: 28951491)

FDN-143301 Canada CIHR; FDN-154288 Canada CIHR

0 (FLO8 protein, S cerevisaie)
0 (Fungal Proteins)
0 (MSS11 protein, S cerevisiae)
0 (Multiprotein Complexes)
0 (Nuclear Proteins)
0 (Saccharomyces cerevisiae Proteins)
0 (Trans-Activators)
0 (Transcription Factors)

Date Created: 20190108 Date Completed: 20190311 Latest Revision: 20200309

20250114

PMC6336345

10.1371/journal.pgen.1007901

30615616