TY - JOUR
T1 - Regulation of gliotoxin biosynthesis and protection in Aspergillus species
AU - de Castro, Patrícia Alves
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.
N1 - Funding Information:
Funding:SãoPauloResearchFoundation (FAPESP)grantnumbers2016/12948-7(PAC), 2017/14159-2(LNAR),and2018/10962-8(GHG) and2016/07870-9(GHG),andConselhoNacional de Desenvolvimento Cientı ´ fico e Tecnolo ´ gico (CNPq)301058/2019-9and404735/2018-5 (GHG),bothfromBrazil.J.L.S.andA.R.are supportedbytheHowardHughesMedicalInstitute throughtheJamesH.GilliamFellowshipsfor AdvancedStudyprogram.AR’slaboratoryreceived additionalsupportfromaDiscoverygrantfrom VanderbiltUniversity,theBurroughsWellcome Fund,theNationalScienceFoundation(DEB-1442113),andtheNationalInstitutesofHealth/ NationalInstituteofAllergyandInfectiousDiseases (R56AI146096andR01AI153356).S.L.K.is supportedbytheNationalInstitutesofHealthvia theNationalCenterforComplementaryand IntegrativeHealth(F31AT010558).A.C.,R.A.G., andC.D.-O.weresupportedbytheFundac ¸ãopara aCiênciaeaTecnologia(FCT)(PTDC/MED-GEN/ 28778/2017,UIDB/50026/2020,andUIDP/50026/ 2020),theNorthernPortugalRegionalOperational Program(NORTE2020),underthePortugal2020 PartnershipAgreement,throughtheEuropean RegionalDevelopmentFund(ERDF)(NORTE-01-0145-FEDER-000039),theICVSScientific MicroscopyPlatform,memberofthenational infrastructurePPBI-PortuguesePlatformof Bioimaging(PPBI-POCI-01-0145-FEDER-022122), theEuropeanUnion’sHorizon2020researchand innovationprogramundergrantagreement 847507,andthe“laCaixa”Foundation(ID 100010434)andFCTundertheagreementLCF/PR/ HP17/52190003.Individualsupportwasprovided byFCT(SFRH/BD/141127/2018toC.D.-O.).We thankUniversidadedoMinho,Portugaland UniversidadedoSãoPaulo,Brazilforproviding supportforthescientificcollaboration(G.H.G.and A.C.,EditalUSP-UMinho2019.Thefundershadno roleinstudydesign,datacollectionandanalysis, decisiontopublish,orpreparationofthe manuscript.
Publisher Copyright:
© 2022 de Castro et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.
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U2 - 10.1371/journal.pgen.1009965
DO - 10.1371/journal.pgen.1009965
M3 - Article
C2 - 35041649
AN - SCOPUS:85123421668
SN - 1553-7390
VL - 18
JO - PLoS Genetics
JF - PLoS Genetics
IS - 1
M1 - e1009965
ER -