Function and Regulation of Cph2 in Candida albicans.
Candida albicans is associated with humans as both a harmless commensal organism and a pathogen. Cph2 is a transcription factor whose DNA binding domain is similar to that of mammalian sterol response element binding proteins (SREBPs). SREBPs are master regulators of cellular cholesterol levels and are highly conserved from fungi to mammals. However, ergosterol biosynthesis is regulated by the zinc finger transcription factor Upc2 in C. albicans and several other yeasts. Cph2 is not necessary for ergosterol biosynthesis but is important for colonization in the murine gastrointestinal (GI) tract. Here we demonstrate that Cph2 is a membrane-associated transcription factor that is processed to release the N-terminal DNA binding domain like SREBPs, but its cleavage is not regulated by cellular levels of ergosterol or oxygen. Chromatin immunoprecipitation sequencing (ChIP-seq) shows that Cph2 binds to the promoters of HMS1 and other components of the regulatory circuit for GI tract colonization. In addition, 50% of Cph2 targets are also bound by Hms1 and other factors of the regulatory circuit. Several common targets function at the head of the glycolysis pathway. Thus, Cph2 is an integral part of the regulatory circuit for GI colonization that regulates glycolytic flux. Transcriptome sequencing (RNA-seq) shows a significant overlap in genes differentially regulated by Cph2 and hypoxia, and Cph2 is important for optimal expression of some hypoxia-responsive genes in glycolysis and the citric acid cycle. We suggest that Cph2 and Upc2 regulate hypoxia-responsive expression in different pathways, consistent with a synthetic lethal defect of the cph2 upc2 double mutant in hypoxia.
Department of Biological Chemistry, University of California, Irvine, California, USA.
Shelley
S
Lane
Department of Computer Science, University of California, Irvine, California, USA Institute for Genomics and Bioinformatics, University of California, Irvine, California, USA Department of Computer Science and Engineering, University of Bologna, Bologna, Italy.
Pietro
P
Di Lena
Department of Biological Chemistry, University of California, Irvine, California, USA.
Kati
K
Tormanen
Department of Biological Chemistry, University of California, Irvine, California, USA Department of Computer Science, University of California, Irvine, California, USA Institute for Genomics and Bioinformatics, University of California, Irvine, California, USA.
Pierre
P
Baldi
Department of Biological Chemistry, University of California, Irvine, California, USA Institute for Genomics and Bioinformatics, University of California, Irvine, California, USA h4liu@uci.edu.
Haoping
H
Liu
D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002176:Candida albicans / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D008969:Molecular Sequence Data; D011485:Protein Binding; D020218:Response Elements; D059467:Transcriptome; D014774:Virulence / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D005656:Fungal Proteins; C435125:CPH2 protein, Candida albicans