Abstract
Small molecule modulators of the Endoplasmic Reticulum glycoprotein folding quality control (ERQC) machinery have broad-spectrum antiviral activity against a number of enveloped viruses and have the potential to rescue secretion of misfolded but active glycoproteins in rare diseases. In vivo assays of candidate inhibitors in mammals are expensive and cannot be afforded at the preliminary stages of drug development programs. The strong conservation of the ERQC machinery across eukaryotes makes transgenic plants an attractive system for low-cost, easy and fast proof-of-concept screening of candidate ERQC inhibitors. The Arabidopsis thaliana immune response is mediated by glycoproteins, the folding of which is controlled by ERQC. We have used the plant response to bacterial peptides as a means of assaying an ERQC inhibitor in vivo. We show that the treatment of the plant with the iminosugar NB-DNJ, which is a known ER α-glucosidase inhibitor in mammals, influences the immune response of the plant to the bacterial peptide elf18 but not to the flagellin-derived flg22 peptide. In the NB-DNJ-treated plant, the responses to elf18 and flg22 treatments closely follow the ones observed for the ER α-glucosidase II impaired plant, At psl5-1. We propose Arabidopsis thaliana as a promising platform for the development of low-cost proof-of-concept in vivo ERQC modulation.
Highlights
Eukaryotic glycoproteins in the cellular secretory pathway require the endoplasmic reticulum (ER) protein-folding quality control (ERQC) machinery in order to fold correctly [1]
We show that treatment with the known ER α-glucosidase iminosugar inhibitor NB-DNJ influences the immune response of the plant to the bacterial elongation factor Tu (EF-Tu) peptide elf18 but not to the bacterial flagellin-derived flg22 peptide
To test the toxicity of NB-DNJ in Arabidopsis thaliana, 15-day-old plants were treated with increasing concentrations of inhibitor, on the basis of a previously developed growth inhibition assay [17]
Summary
Eukaryotic glycoproteins in the cellular secretory pathway require the endoplasmic reticulum (ER) protein-folding quality control (ERQC) machinery in order to fold correctly [1]. In vitro screens have been proposed to offer several advantages over phenotype-based in vivo methods as a starting point for drug repositioning [13] but modulators of the activity of ER α-glucosidases need to cross both the plasma- and ER-membranes This challenge makes cheap and easy in vivo screening a more appealing strategy towards the development of compounds that possess both activity and the ability to reach their cellular targets in the ER lumen. We show that treatment with the known ER α-glucosidase iminosugar inhibitor NB-DNJ influences the immune response of the plant to the bacterial EF-Tu peptide elf but not to the bacterial flagellin-derived flg peptide. We cannot rule out the possibility that the molecule interferes with either other secretory pathway components causing mis-folding and/or mis-localization of elf18-receptor, or with any of the components of the elf response
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
