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Modulation of histone H3 lysine 56 acetylation as an antifungal therapeutic strategy

Nature Medicine volume 16, pages 774–780 (2010)Cite this article

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Abstract

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.

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Figure 1: H3K56 acetylation modulates genotoxic and fungicidal agent sensitivity in C. albicans.
Figure 2: HST3 controls H3K56 deacetylation and is required for cell viability in C. albicans.
Figure 3: HST3 repression triggers abnormal changes in cell morphology and DNA staining.
Figure 4: HST3 repression and nicotinamide are cytotoxic to C. albicans strains that express RTT109.
Figure 5: Nicotinamide inhibits growth of several clinically important pathogenic fungi.
Figure 6: Modulation of H3K56ac levels reduces virulence in a mouse model of C. albicans infection.

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Acknowledgements

We are grateful to T. Roemer (Merck Research Laboratory) for providing strain CaSS1 and plasmids pHIS3 and pSAT-Tet, G. St-Germain (Laboratoire de santé publique du Québec) for strains MY067497, MY067743, MY070362, MY070589, MY069520, MY070954, MY070968 and MY070627, C. Restieri and M. Laverdière (Hôpital Maisonneuve-Rosemont) for strain 372.73374.1, C. Bachewich (Concordia University) for strain R153 and T. Edlind (Drexel University College of Medicine) for strain 20464. We are indebted to T. Roemer and M. Whiteway for critical reading of the manuscript. We thank F. Malenfant, J. Leroy, M. Mercier and P. Liscourt for excellent assistance in mouse handling. We are also grateful for the availability of the Candida Genome Database. This work was supported by research grants from the Canadian Institutes of Health Research to M.R. (CTP-79843, III-94587), A.M. (CTP-79843) and A.V. (CTP-79392) and from the National Science and Engineering Research Council of Canada to P.T. (STGP-322143-05). This is National Research Council of Canada publication number 52756. The Institute for Research in Immunology and Cancer is supported by funds from the Canadian Center of Excellence in Commercialization and Research, the Canadian Foundation for Innovation, and the Fonds de la Recherche en Santé du Québec.

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  1. Hugo Wurtele and Sarah Tsao: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Canada

    Hugo Wurtele, Sarah Tsao, Guylaine Lépine, Paul Drogaris, Eun-Hye Lee, Pierre Thibault, Alain Verreault & Martine Raymond

  2. Biotechnology Research Institute, National Research Council of Canada, Montreal, Canada

    Alaka Mullick & Jessy Tremblay

  3. Département de Microbiologie et Immunologie, Université de Montréal, Montreal, Canada

    Alaka Mullick & Jessy Tremblay

  4. Département de Chimie, Université de Montréal, Montreal, Canada

    Pierre Thibault

  5. Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montreal, Canada

    Alain Verreault

  6. Département de Biochimie, Université de Montréal, Montreal, Canada

    Martine Raymond

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Contributions

H.W. and S.T. designed and performed most experiments; G.L. constructed the yeast strains used in this study; J.T. and S.T. performed the fungal load and cytokine analyses; A.M. and M.R. designed and supervised the mouse studies; P.D., P.T. and A.V. designed and performed mass spectrometry experiments; E.-H.L. provided technical support; all authors participated in manuscript preparation; M.R. and A.V. supervised the study.

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Correspondence to Alain Verreault or Martine Raymond.

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Wurtele, H., Tsao, S., Lépine, G. et al. Modulation of histone H3 lysine 56 acetylation as an antifungal therapeutic strategy. Nat Med 16, 774–780 (2010). https://doi.org/10.1038/nm.2175

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