title: The bHLH transcription factor BIS1 controls the iridoid branch of the monoterpenoid indole alkaloid pathway in Catharanthus roseus.
abstract: Plants make specialized bioactive metabolites to defend themselves against attackers. The conserved control mechanisms are based on transcriptional activation of the respective plant species-specific biosynthetic pathways by the phytohormone jasmonate. Knowledge of the transcription factors involved, particularly in terpenoid biosynthesis, remains fragmentary. By transcriptome analysis and functional screens in the medicinal plant Catharanthus roseus (Madagascar periwinkle), the unique source of the monoterpenoid indole alkaloid (MIA)-type anticancer drugs vincristine and vinblastine, we identified a jasmonate-regulated basic helix-loop-helix (bHLH) transcription factor from clade IVa inducing the monoterpenoid branch of the MIA pathway. The bHLH iridoid synthesis 1 (BIS1) transcription factor transactivated the expression of all of the genes encoding the enzymes that catalyze the sequential conversion of the ubiquitous terpenoid precursor geranyl diphosphate to the iridoid loganic acid. BIS1 acted in a complementary manner to the previously characterized ethylene response factor Octadecanoid derivative-Responsive Catharanthus APETALA2-domain 3 (ORCA3) that transactivates the expression of several genes encoding the enzymes catalyzing the conversion of loganic acid to the downstream MIAs. In contrast to ORCA3, overexpression of BIS1 was sufficient to boost production of high-value iridoids and MIAs in C. roseus suspension cell cultures. Hence, BIS1 might be a metabolic engineering tool to produce sustainably high-value MIAs in C. roseus plants or cultures.
authors.affiliation: Department of Plant Systems Biology, Flanders Institute for Biotechnology (VIB), 9052 Gent, Belgium; Department of Plant Biotechnology and Bioinformatics, Ghent University, 9052 Gent, Belgium;
authors.forename: Alex
authors.initials: A
authors.lastname: Van Moerkercke
authors.affiliation: Institute of Biology, Leiden University, 2300 RA Leiden, The Netherlands;
authors.forename: Priscille
authors.initials: P
authors.lastname: Steensma
authors.affiliation: Department of Plant Systems Biology, Flanders Institute for Biotechnology (VIB), 9052 Gent, Belgium; Department of Plant Biotechnology and Bioinformatics, Ghent University, 9052 Gent, Belgium;
authors.forename: Fabian
authors.initials: F
authors.lastname: Schweizer
authors.affiliation: Department of Plant Systems Biology, Flanders Institute for Biotechnology (VIB), 9052 Gent, Belgium; Department of Plant Biotechnology and Bioinformatics, Ghent University, 9052 Gent, Belgium;
authors.forename: Jacob
authors.identifier: http://orcid.org/0000-0002-1134-9238
authors.initials: J
authors.lastname: Pollier
authors.affiliation: Institute of Biology, Leiden University, 2300 RA Leiden, The Netherlands;
authors.forename: Ivo
authors.initials: I
authors.lastname: Gariboldi
authors.affiliation: Department of Biological Chemistry, John Innes Centre, Norwich NR4 7UH, United Kingdom;
authors.forename: Richard
authors.initials: R
authors.lastname: Payne
authors.affiliation: Department of Plant Systems Biology, Flanders Institute for Biotechnology (VIB), 9052 Gent, Belgium; Department of Plant Biotechnology and Bioinformatics, Ghent University, 9052 Gent, Belgium;
authors.forename: Robin
authors.initials: R
authors.lastname: Vanden Bossche
authors.affiliation: Department of Plant Systems Biology, Flanders Institute for Biotechnology (VIB), 9052 Gent, Belgium; Department of Plant Biotechnology and Bioinformatics, Ghent University, 9052 Gent, Belgium;
authors.forename: Karel
authors.initials: K
authors.lastname: Miettinen
authors.affiliation: Institute of Biology, Leiden University, 2300 RA Leiden, The Netherlands;
authors.forename: Javiera
authors.initials: J
authors.lastname: Espoz
authors.affiliation: Institute of Biology, Leiden University, 2300 RA Leiden, The Netherlands;
authors.forename: Purin Candra
authors.initials: PC
authors.lastname: Purnama
authors.affiliation: Department of Biological Chemistry, John Innes Centre, Norwich NR4 7UH, United Kingdom;
authors.forename: Franziska
authors.initials: F
authors.lastname: Kellner
authors.affiliation: VTT Technical Research Centre of Finland Ltd., FIN-02044 VTT, Espoo, Finland.
authors.forename: Tuulikki
authors.initials: T
authors.lastname: Seppänen-Laakso
authors.affiliation: Department of Biological Chemistry, John Innes Centre, Norwich NR4 7UH, United Kingdom;
authors.forename: Sarah E
authors.initials: SE
authors.lastname: O'Connor
authors.affiliation: VTT Technical Research Centre of Finland Ltd., FIN-02044 VTT, Espoo, Finland.
authors.forename: Heiko
authors.initials: H
authors.lastname: Rischer
authors.affiliation: Institute of Biology, Leiden University, 2300 RA Leiden, The Netherlands;
authors.forename: Johan
authors.initials: J
authors.lastname: Memelink
authors.affiliation: Department of Plant Systems Biology, Flanders Institute for Biotechnology (VIB), 9052 Gent, Belgium; Department of Plant Biotechnology and Bioinformatics, Ghent University, 9052 Gent, Belgium; algoo@psb.vib-ugent.be.
authors.forename: Alain
authors.identifier: http://orcid.org/0000-0002-1599-551X
authors.initials: A
authors.lastname: Goossens
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D030008:Catharanthus / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D017343:Genes, Plant; D026121:Indole Alkaloids / Q000378:metabolism*; D008969:Molecular Sequence Data; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D026121:Indole Alkaloids
keywords: Catharanthus roseus; Madagascar periwinkle; basic helix loop helix; iridoids; jasmonate