The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species

Xie, Jinhong; Rybak, Jeffrey M.; Martin-Vicente, Adela; Guruceaga, Xabier; Thorn, Harrison I.; Nywening, Ashley V.; Ge, Wenbo; Parker, Josie E.; Kelly, Steven; Rogers, P. David; Fortwendel, Jarrod R.

doi:10.1038/s41467-024-48767-3

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The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species

Jinhong Xie

, Jeffrey M. Rybak

, Adela Martin-Vicente, Xabier Guruceaga

, Harrison I. Thorn

, Ashley V. Nywening, Wenbo Ge, Josie E. Parker

, Steven Kelly, P. David Rogers, Jarrod R. Fortwendel

Nature Communications, Volume: 15, Issue: 1

Swansea University Author: Steven Kelly

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DOI (Published version): 10.1038/s41467-024-48767-3

Abstract

Triazoles, the most widely used class of antifungal drugs, inhibit the biosynthesis of ergosterol, a crucial component of the fungal plasma membrane. Inhibition of a separate ergosterol biosynthetic step, catalyzed by the sterol C-24 methyltransferase Erg6, reduces the virulence of pathogenic yeasts...

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Published in:	Nature Communications
ISSN:	2041-1723
Published:	Springer Science and Business Media LLC 2024
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa67192
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spelling	v2 67192 2024-07-26 The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species b17cebaf09b4d737b9378a3581e3de93 Steven Kelly Steven Kelly true false 2024-07-26 Triazoles, the most widely used class of antifungal drugs, inhibit the biosynthesis of ergosterol, a crucial component of the fungal plasma membrane. Inhibition of a separate ergosterol biosynthetic step, catalyzed by the sterol C-24 methyltransferase Erg6, reduces the virulence of pathogenic yeasts, but its effects on filamentous fungal pathogens like Aspergillus fumigatus remain unexplored. Here, we show that the lipid droplet-associated enzyme Erg6 is essential for the viability of A. fumigatus and other Aspergillus species, including A. lentulus, A. terreus, and A. nidulans. Downregulation of erg6 causes loss of sterol-rich membrane domains required for apical extension of hyphae, as well as altered sterol profiles consistent with the Erg6 enzyme functioning upstream of the triazole drug target, Cyp51A/Cyp51B. Unexpectedly, erg6-repressed strains display wild-type susceptibility against the ergosterol-active triazole and polyene antifungals. Finally, we show that erg6 repression results in significant reduction in mortality in a murine model of invasive aspergillosis. Taken together with recent studies, our work supports Erg6 as a potentially pan-fungal drug target. Journal Article Nature Communications 15 1 Springer Science and Business Media LLC 2041-1723 20 5 2024 2024-05-20 10.1038/s41467-024-48767-3 COLLEGE NANME COLLEGE CODE Swansea University This work was supported by National Institutes of Health (NIH) / National Institute of Allergy and Infectious Diseases (NIAID) grants R01 AI158442 (JRF) and R01 AI143197 (JRF/PDR). The authors would also like to thank Nathan P. Wiederhold, PharmD at the Fungus Testing laboratory for providing the A. lentulus isolate used in this study. 2024-08-29T13:54:27.0012552 2024-07-26T12:14:28.0127252 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Jinhong Xie 0000-0002-8994-6606 1 Jeffrey M. Rybak 0000-0002-9317-0935 2 Adela Martin-Vicente 3 Xabier Guruceaga 0000-0003-3258-2482 4 Harrison I. Thorn 0009-0003-2546-8400 5 Ashley V. Nywening 6 Wenbo Ge 7 Josie E. Parker 0000-0002-3855-4194 8 Steven Kelly 9 P. David Rogers 10 Jarrod R. Fortwendel 0000-0003-2301-4272 11 67192__31174__360561c40d7649c0bd8d02d1fa51c4ca.pdf 67192.VoR.pdf 2024-08-29T13:40:22.7295367 Output 4584898 application/pdf Version of Record true © The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License. true eng http://creativecommons.org/licenses/by/4.0/
title	The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species
spellingShingle	The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species Steven Kelly
title_short	The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species
title_full	The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species
title_fullStr	The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species
title_full_unstemmed	The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species
title_sort	The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species
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author_id_fullname_str_mv	b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly
author	Steven Kelly
author2	Jinhong Xie Jeffrey M. Rybak Adela Martin-Vicente Xabier Guruceaga Harrison I. Thorn Ashley V. Nywening Wenbo Ge Josie E. Parker Steven Kelly P. David Rogers Jarrod R. Fortwendel
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container_title	Nature Communications
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description	Triazoles, the most widely used class of antifungal drugs, inhibit the biosynthesis of ergosterol, a crucial component of the fungal plasma membrane. Inhibition of a separate ergosterol biosynthetic step, catalyzed by the sterol C-24 methyltransferase Erg6, reduces the virulence of pathogenic yeasts, but its effects on filamentous fungal pathogens like Aspergillus fumigatus remain unexplored. Here, we show that the lipid droplet-associated enzyme Erg6 is essential for the viability of A. fumigatus and other Aspergillus species, including A. lentulus, A. terreus, and A. nidulans. Downregulation of erg6 causes loss of sterol-rich membrane domains required for apical extension of hyphae, as well as altered sterol profiles consistent with the Erg6 enzyme functioning upstream of the triazole drug target, Cyp51A/Cyp51B. Unexpectedly, erg6-repressed strains display wild-type susceptibility against the ergosterol-active triazole and polyene antifungals. Finally, we show that erg6 repression results in significant reduction in mortality in a murine model of invasive aspergillosis. Taken together with recent studies, our work supports Erg6 as a potentially pan-fungal drug target.
published_date	2024-05-20T13:54:25Z
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The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species

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