title: Decatransin, a new natural product inhibiting protein translocation at the Sec61/SecYEG translocon.
abstract: A new cyclic decadepsipeptide was isolated from Chaetosphaeria tulasneorum with potent bioactivity on mammalian and yeast cells. Chemogenomic profiling in S. cerevisiae indicated that the Sec61 translocon complex, the machinery for protein translocation and membrane insertion at the endoplasmic reticulum, is the target. The profiles were similar to those of cyclic heptadepsipeptides of a distinct chemotype (including HUN-7293 and cotransin) that had previously been shown to inhibit cotranslational translocation at the mammalian Sec61 translocon. Unbiased, genome-wide mutagenesis followed by full-genome sequencing in both fungal and mammalian cells identified dominant mutations in Sec61p (yeast) or Sec61α1 (mammals) that conferred resistance. Most, but not all, of these mutations affected inhibition by both chemotypes, despite an absence of structural similarity. Biochemical analysis confirmed inhibition of protein translocation into the endoplasmic reticulum of both co- and post-translationally translocated substrates by both chemotypes, demonstrating a mechanism independent of a translating ribosome. Most interestingly, both chemotypes were found to also inhibit SecYEG, the bacterial Sec61 translocon homolog. We suggest 'decatransin' as the name for this new decadepsipeptide translocation inhibitor.
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.
authors.forename: Tina
authors.initials: T
authors.lastname: Junne
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Joanne
authors.initials: J
authors.lastname: Wong
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Studer
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Aust
authors.affiliation: Howard Hughes Medical Institute, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Benedikt W
authors.initials: BW
authors.lastname: Bauer
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Beibel
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Bhupinder
authors.initials: B
authors.lastname: Bhullar
authors.affiliation: Congenomics, LLC, 60 Gates Farm Road, Glastonbury, CT 06033, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Bruccoleri
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Jürg
authors.initials: J
authors.lastname: Eichenberger
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Estoppey
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Hartmann
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Britta
authors.initials: B
authors.lastname: Knapp
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Krastel
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Melin
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Oakeley
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Oberer
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Ralph
authors.initials: R
authors.lastname: Riedl
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Guglielmo
authors.initials: G
authors.lastname: Roma
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Schuierer
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Frank
authors.initials: F
authors.lastname: Petersen
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Tallarico
authors.affiliation: Howard Hughes Medical Institute, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Tom A
authors.initials: TA
authors.lastname: Rapoport
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland martin.spiess@unibas.ch dominic.hoepfner@novartis.com.
authors.forename: Martin
authors.initials: M
authors.lastname: Spiess
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel, Switzerland martin.spiess@unibas.ch dominic.hoepfner@novartis.com.
authors.forename: Dominic
authors.initials: D
authors.lastname: Hoepfner
mesh_terms: D000818:Animals; D001203:Ascomycota / Q000378:metabolism; D001688:Biological Products / Q000494:pharmacology*; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D045325:HCT116 Cells; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects*; D000069816:SEC Translocation Channels; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*
chemical_list: D001688:Biological Products; C097977:HUN 7293; D008565:Membrane Proteins; D010456:Peptides, Cyclic; D000069816:SEC Translocation Channels; D029701:Saccharomyces cerevisiae Proteins; C502316:cotransin
keywords: Cotransin; Endoplasmic reticulum; Haploinsufficiency profiling; SEC61; Target identification; Translocation inhibition