Modulation of histone H3 lysine 56 acetylation as an antifungal therapeutic strategy.
Candida albicans is a major fungal pathogen that causes serious systemic and mucosal infections in immunocompromised individuals. In yeast, histone H3 Lys56 acetylation (H3K56ac) is an abundant modification regulated by enzymes that have fungal-specific properties, making them appealing targets for antifungal therapy. Here we demonstrate that H3K56ac in C. albicans is regulated by the RTT109 and HST3 genes, which respectively encode the H3K56 acetyltransferase (Rtt109p) and deacetylase (Hst3p). We show that reduced levels of H3K56ac sensitize C. albicans to genotoxic and antifungal agents. Inhibition of Hst3p activity by conditional gene repression or nicotinamide treatment results in a loss of cell viability associated with abnormal filamentous growth, histone degradation and gross aberrations in DNA staining. We show that genetic or pharmacological alterations in H3K56ac levels reduce virulence in a mouse model of C. albicans infection. Our results demonstrate that modulation of H3K56ac is a unique strategy for treatment of C. albicans and, possibly, other fungal infections.
Wurtele
Hugo
H
Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Canada.
Tsao
Sarah
S
Lépine
Guylaine
G
Mullick
Alaka
A
Tremblay
Jessy
J
Drogaris
Paul
P
Lee
Eun-Hye
EH
Thibault
Pierre
P
Verreault
Alain
A
Raymond
Martine
M
D000107:Acetylation; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000201:enzymology* / Q000472:pathogenicity*; D002177:Candidiasis / Q000201:enzymology* / Q000235:genetics; D002470:Cell Survival; D016503:Drug Delivery Systems; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D051379:Mice; D009536:Niacinamide / Q000494:pharmacology; D014774:Virulence
D000935:Antifungal Agents; D005656:Fungal Proteins; D006657:Histones; D009536:Niacinamide; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases