Regulation of gliotoxin biosynthesis and protection in Aspergillus species

Castro PA de; Ana Cristina Colabardini; Maísa Moraes; Maria Augusta Crivelente Horta; Sonja L. Knowles; Huzefa A. Raja; Nicholas H. Oberlies; Yasuji Koyama; Masahiro Ogawa; Katsuya Gomi; Jacob L. Steenwyk; Antonis Rokas; Relber A. Gonçales; Cláudio Duarte-Oliveira; Agostinho Carvalho; Laure N.A. Ries; Gustavo H. Goldman

doi:10.1371/journal.pgen.1009965

Regulation of gliotoxin biosynthesis and protection in Aspergillus species

Castro PA de
, Ana Cristina Colabardini
, Maísa Moraes
, Maria Augusta Crivelente Horta
, Sonja L. Knowles
, Huzefa A. Raja
, Nicholas H. Oberlies
, Yasuji Koyama
, Masahiro Ogawa
, Katsuya Gomi
, Jacob L. Steenwyk
, Antonis Rokas
, Relber A. Gonçales
, Cláudio Duarte-Oliveira
, Agostinho Carvalho
, Laure N.A. Ries^*
, Gustavo H. Goldman^*

^*Corresponding author for this work

School of Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

Aspergillus fumigatus causes a range of human and animal diseases collectively known as aspergillosis. A. fumigatus possesses and expresses a range of genetic determinants of virulence, which facilitate colonisation and disease progression, including the secretion of mycotoxins. Gliotoxin (GT) is the best studied A. fumigatus mycotoxin with a wide range of known toxic effects that impair human immune cell function. GT is also highly toxic to A. fumigatus and this fungus has evolved self-protection mechanisms that include (i) the GT efflux pump GliA, (ii) the GT neutralising enzyme GliT, and (iii) the negative regulation of GT biosynthesis by the bis-thiomethyltransferase GtmA. The transcription factor (TF) RglT is the main regulator of GliT and this GT protection mechanism also occurs in the non-GT producing fungus A. nidulans. However, the A. nidulans genome does not encode GtmA and GliA. This work aimed at analysing the transcriptional response to exogenous GT in A. fumigatus and A. nidulans, two distantly related Aspergillus species, and to identify additional components required for GT protection. RNA-sequencing shows a highly different transcriptional response to exogenous GT with the RglT-dependent regulon also significantly differing between A. fumigatus and A. nidulans. However, we were able to observe homologs whose expression pattern was similar in both species (43 RglT-independent and 11 RglT-dependent). Based on this approach, we identified a novel RglT-dependent methyltranferase, MtrA, involved in GT protection. Taking into consideration the occurrence of RglT-independent modulated genes, we screened an A. fumigatus deletion library of 484 transcription factors (TFs) for sensitivity to GT and identified 15 TFs important for GT self-protection. Of these, the TF KojR, which is essential for kojic acid biosynthesis in Aspergillus oryzae, was also essential for virulence and GT biosynthesis in A. fumigatus, and for GT protection in A. fumigatus, A. nidulans, and A. oryzae. KojR regulates rglT, gliT, gliJ expression and sulfur metabolism in Aspergillus species. Together, this study identified conserved components required for GT protection in Aspergillus species.

Original language	English
Pages (from-to)	e1009965-e1009965
Number of pages	0
Journal	PLoS Genetics
Volume	18
Issue number	1
DOIs	https://doi.org/10.1371/journal.pgen.1009965
Publication status	E-pub ahead of print - 18 Jan 2022

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de, C. PA., Colabardini, A. C., Moraes, M., Horta, M. A. C., Knowles, S. L., Raja, H. A., Oberlies, N. H., Koyama, Y., Ogawa, M., Gomi, K., Steenwyk, J. L., Rokas, A., Gonçales, R. A., Duarte-Oliveira, C., Carvalho, A., Ries, L. N. A., & Goldman, G. H. (2022). Regulation of gliotoxin biosynthesis and protection in Aspergillus species. PLoS Genetics, 18(1), e1009965-e1009965. Advance online publication. https://doi.org/10.1371/journal.pgen.1009965

@article{80fd0311d4fc4b3a893fd3a541ea1ee7,

title = "Regulation of gliotoxin biosynthesis and protection in Aspergillus species",

abstract = "Aspergillus fumigatus causes a range of human and animal diseases collectively known as aspergillosis. A. fumigatus possesses and expresses a range of genetic determinants of virulence, which facilitate colonisation and disease progression, including the secretion of mycotoxins. Gliotoxin (GT) is the best studied A. fumigatus mycotoxin with a wide range of known toxic effects that impair human immune cell function. GT is also highly toxic to A. fumigatus and this fungus has evolved self-protection mechanisms that include (i) the GT efflux pump GliA, (ii) the GT neutralising enzyme GliT, and (iii) the negative regulation of GT biosynthesis by the bis-thiomethyltransferase GtmA. The transcription factor (TF) RglT is the main regulator of GliT and this GT protection mechanism also occurs in the non-GT producing fungus A. nidulans. However, the A. nidulans genome does not encode GtmA and GliA. This work aimed at analysing the transcriptional response to exogenous GT in A. fumigatus and A. nidulans, two distantly related Aspergillus species, and to identify additional components required for GT protection. RNA-sequencing shows a highly different transcriptional response to exogenous GT with the RglT-dependent regulon also significantly differing between A. fumigatus and A. nidulans. However, we were able to observe homologs whose expression pattern was similar in both species (43 RglT-independent and 11 RglT-dependent). Based on this approach, we identified a novel RglT-dependent methyltranferase, MtrA, involved in GT protection. Taking into consideration the occurrence of RglT-independent modulated genes, we screened an A. fumigatus deletion library of 484 transcription factors (TFs) for sensitivity to GT and identified 15 TFs important for GT self-protection. Of these, the TF KojR, which is essential for kojic acid biosynthesis in Aspergillus oryzae, was also essential for virulence and GT biosynthesis in A. fumigatus, and for GT protection in A. fumigatus, A. nidulans, and A. oryzae. KojR regulates rglT, gliT, gliJ expression and sulfur metabolism in Aspergillus species. Together, this study identified conserved components required for GT protection in Aspergillus species.",

author = "de, \{Castro PA\} and Colabardini, \{Ana Cristina\} and Ma{\'i}sa Moraes and Horta, \{Maria Augusta Crivelente\} and Knowles, \{Sonja L.\} and Raja, \{Huzefa A.\} and Oberlies, \{Nicholas H.\} and Yasuji Koyama and Masahiro Ogawa and Katsuya Gomi and Steenwyk, \{Jacob L.\} and Antonis Rokas and Gon{\c c}ales, \{Relber A.\} and Cl{\'a}udio Duarte-Oliveira and Agostinho Carvalho and Ries, \{Laure N.A.\} and Goldman, \{Gustavo H.\}",

year = "2022",

month = jan,

day = "18",

doi = "10.1371/journal.pgen.1009965",

language = "English",

volume = "18",

pages = "e1009965--e1009965",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "1",

}

de, CPA, Colabardini, AC, Moraes, M, Horta, MAC, Knowles, SL, Raja, HA, Oberlies, NH, Koyama, Y, Ogawa, M, Gomi, K, Steenwyk, JL, Rokas, A, Gonçales, RA, Duarte-Oliveira, C, Carvalho, A, Ries, LNA & Goldman, GH 2022, 'Regulation of gliotoxin biosynthesis and protection in Aspergillus species', PLoS Genetics, vol. 18, no. 1, pp. e1009965-e1009965. https://doi.org/10.1371/journal.pgen.1009965

TY - JOUR

T1 - Regulation of gliotoxin biosynthesis and protection in Aspergillus species

AU - de, Castro PA

AU - Colabardini, Ana Cristina

AU - Moraes, Maísa

AU - Horta, Maria Augusta Crivelente

AU - Knowles, Sonja L.

AU - Raja, Huzefa A.

AU - Oberlies, Nicholas H.

AU - Koyama, Yasuji

AU - Ogawa, Masahiro

AU - Gomi, Katsuya

AU - Steenwyk, Jacob L.

AU - Rokas, Antonis

AU - Gonçales, Relber A.

AU - Duarte-Oliveira, Cláudio

AU - Carvalho, Agostinho

AU - Ries, Laure N.A.

AU - Goldman, Gustavo H.

PY - 2022/1/18

Y1 - 2022/1/18

N2 - Aspergillus fumigatus causes a range of human and animal diseases collectively known as aspergillosis. A. fumigatus possesses and expresses a range of genetic determinants of virulence, which facilitate colonisation and disease progression, including the secretion of mycotoxins. Gliotoxin (GT) is the best studied A. fumigatus mycotoxin with a wide range of known toxic effects that impair human immune cell function. GT is also highly toxic to A. fumigatus and this fungus has evolved self-protection mechanisms that include (i) the GT efflux pump GliA, (ii) the GT neutralising enzyme GliT, and (iii) the negative regulation of GT biosynthesis by the bis-thiomethyltransferase GtmA. The transcription factor (TF) RglT is the main regulator of GliT and this GT protection mechanism also occurs in the non-GT producing fungus A. nidulans. However, the A. nidulans genome does not encode GtmA and GliA. This work aimed at analysing the transcriptional response to exogenous GT in A. fumigatus and A. nidulans, two distantly related Aspergillus species, and to identify additional components required for GT protection. RNA-sequencing shows a highly different transcriptional response to exogenous GT with the RglT-dependent regulon also significantly differing between A. fumigatus and A. nidulans. However, we were able to observe homologs whose expression pattern was similar in both species (43 RglT-independent and 11 RglT-dependent). Based on this approach, we identified a novel RglT-dependent methyltranferase, MtrA, involved in GT protection. Taking into consideration the occurrence of RglT-independent modulated genes, we screened an A. fumigatus deletion library of 484 transcription factors (TFs) for sensitivity to GT and identified 15 TFs important for GT self-protection. Of these, the TF KojR, which is essential for kojic acid biosynthesis in Aspergillus oryzae, was also essential for virulence and GT biosynthesis in A. fumigatus, and for GT protection in A. fumigatus, A. nidulans, and A. oryzae. KojR regulates rglT, gliT, gliJ expression and sulfur metabolism in Aspergillus species. Together, this study identified conserved components required for GT protection in Aspergillus species.

AB - Aspergillus fumigatus causes a range of human and animal diseases collectively known as aspergillosis. A. fumigatus possesses and expresses a range of genetic determinants of virulence, which facilitate colonisation and disease progression, including the secretion of mycotoxins. Gliotoxin (GT) is the best studied A. fumigatus mycotoxin with a wide range of known toxic effects that impair human immune cell function. GT is also highly toxic to A. fumigatus and this fungus has evolved self-protection mechanisms that include (i) the GT efflux pump GliA, (ii) the GT neutralising enzyme GliT, and (iii) the negative regulation of GT biosynthesis by the bis-thiomethyltransferase GtmA. The transcription factor (TF) RglT is the main regulator of GliT and this GT protection mechanism also occurs in the non-GT producing fungus A. nidulans. However, the A. nidulans genome does not encode GtmA and GliA. This work aimed at analysing the transcriptional response to exogenous GT in A. fumigatus and A. nidulans, two distantly related Aspergillus species, and to identify additional components required for GT protection. RNA-sequencing shows a highly different transcriptional response to exogenous GT with the RglT-dependent regulon also significantly differing between A. fumigatus and A. nidulans. However, we were able to observe homologs whose expression pattern was similar in both species (43 RglT-independent and 11 RglT-dependent). Based on this approach, we identified a novel RglT-dependent methyltranferase, MtrA, involved in GT protection. Taking into consideration the occurrence of RglT-independent modulated genes, we screened an A. fumigatus deletion library of 484 transcription factors (TFs) for sensitivity to GT and identified 15 TFs important for GT self-protection. Of these, the TF KojR, which is essential for kojic acid biosynthesis in Aspergillus oryzae, was also essential for virulence and GT biosynthesis in A. fumigatus, and for GT protection in A. fumigatus, A. nidulans, and A. oryzae. KojR regulates rglT, gliT, gliJ expression and sulfur metabolism in Aspergillus species. Together, this study identified conserved components required for GT protection in Aspergillus species.

U2 - 10.1371/journal.pgen.1009965

DO - 10.1371/journal.pgen.1009965

M3 - Article

SN - 1553-7390

VL - 18

SP - e1009965-e1009965

JO - PLoS Genetics

JF - PLoS Genetics

IS - 1

ER -

Regulation of gliotoxin biosynthesis and protection in Aspergillus species

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