Histone acetyltransferase Rtt109 is required for Candida albicans pathogenesis

Abstract

Candida albicans is a ubiquitous opportunistic pathogen that is the most prevalent cause of hospital-acquired fungal infections. In mammalian hosts, C. albicans is engulfed by phagocytes that attack the pathogen with DNA-damaging reactive oxygen species (ROS). Acetylation of histone H3 lysine 56 (H3K56) by the fungal-specific histone acetyltransferase Rtt109 is important for yeast model organisms to survive DNA damage and maintain genome integrity. To assess the importance of Rtt109 for C. albicans pathogenicity, we deleted the predicted homolog of Rtt109 in the clinical C. albicans isolate, SC5314. C. albicans rtt109 −/− mutant cells lack acetylated H3K56 (H3K56ac) and are hypersensitive to genotoxic agents. Additionally, rtt109 −/− mutant cells constitutively display increased H2A S129 phosphorylation and elevated DNA repair gene expression, consistent with endogenous DNA damage. Importantly, C. albicans rtt109 −/− cells are significantly less pathogenic in mice and more susceptible to killing by macrophages in vitro than are wild-type cells. Via pharmacological inhibition of the host NADPH oxidase enzyme, we show that the increased sensitivity of rtt109 −/− cells to macrophages depends on the host's ability to generate ROS, providing a mechanistic link between the drug sensitivity, gene expression, and pathogenesis phenotypes. We conclude that Rtt109 is particularly important for fungal pathogenicity, suggesting a unique target for therapeutic antifungal compounds.acetylation | chromatin | fungal pathogenesis | DNA damage resistance | macrophage

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

“…The link between the SAGA coactivator complex and Hsp90 may help to further explain the importance of this complex in regulating azole resistance. A recent study showed that while the HAT enzyme Rtt109 has no impact on azole sensitivity, it is required for C. albicans pathogenesis in a mouse model of infection (344,634). This is at least partially due to the increased susceptibility to macrophages and the altered profile of metabolic gene expression of the rtt109 homozygous deletion mutant (344) as well as a weaker inflammatory response induced by the rtt109 mutant (634).…”

Direct effects of non-antifungal agents used in cancer chemotherapy and organ transplantation on the development and virulence ofCandidaandAspergillusspecies

“…Finally, reduced levels of H3K56ac activity (regulated by the C. albicans RTT109 gene) have sensitized C. albicans to hydroxyurea, the azoles, and echinocandins and are associated with attenuated C. albicans virulence in mice. 113,120 Inhibition of Hst3p in C. albicans results in loss of cell viability with abnormal filamentous growth. 113 Researchers have tested the activity of at least one new HDACi, MG-CD290, against a range of Candida spp.…”

Catalytic activation of histone acetyltransferase Rtt109 by a histone chaperone

“…Distinct histone chaperones (Vps75 and Asf1) help direct Rtt109 substrate selection for different biological processes, and each stimulates the acetyltransferase activity of Rtt109 (8)(9)(10)(11). In Candida albicans, Rtt109 is required for pathogenesis and, thus, could provide a unique target for antifungal therapies (12). Notably, Rtt109 lacks sequence homology to previously characterized HATs (11,(13)(14)(15), although Rtt109's structure has revealed similarity to the mammalian HAT p300 (KAT3B) (16).…”