Candida albicans SET1 encodes a histone 3 lysine 4 methyltransferase that contributes to the pathogenesis of invasive candidiasis.
Candida albicans causes diverse mucosal and systemic diseases. Although this versatility likely depends upon carefully co-ordinated gene expression, epigenetic regulation in C. albicans remains poorly characterized. Screening a genomic expression library, we identified C. albicans Set1p as an immunogenic protein with homology to a lysine histone methyltransferase of Saccharomyces cerevisiae. In this study, we demonstrated that total immunoglobulin, IgG and IgM titers against a unique Set1p N-terminal fragment were significantly higher among patients with disseminated candidiasis (DC) or oropharyngeal candidiasis than controls. Disruption of SET1 resulted in complete loss of methylation of histone 3 at lysine residue 4, hyperfilamentous growth under embedded conditions, less negative cell surface charges and diminished adherence to epithelial cells, effects that were reversed upon gene re-insertion at a disrupted locus. During murine DC, the null mutant was associated with prolonged survival and lower tissue burdens. Taken together, our findings suggest that SET1 regulates multiple processes important to the pathogenesis of candidiasis. The Set1p N-terminal fragment does not exhibit significant homology to eukaryotic or microbial proteins, and might represent a novel therapeutic, preventive or diagnostic target.
Raman
Suresh Babu
SB
Department of Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Nguyen
M Hong
MH
Zhang
Zongde
Z
Cheng
Shaoji
S
Jia
Hong Yan
HY
Weisner
Nghe
N
Iczkowski
Kenneth
K
Clancy
Cornelius J
CJ
D000818:Animals; D002176:Candida albicans / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity*; D002177:Candidiasis / Q000382:microbiology / Q000401:mortality / Q000503:physiopathology*; D002180:Candidiasis, Oral / Q000382:microbiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D019073:HT29 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014774:Virulence
D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D011495:Histone-Lysine N-Methyltransferase; C411250:SET1 protein, S cerevisiae