In planta preliminary screening of ER glycoprotein folding quality control (ERQC) modulators
Marti L., Lia A., Reca IB., Roversi P., Santino A., Zitzmann N.
The 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 the secretion of misfolded but active glycoproteins in rare diseases. The in vivo screening of such inhibitors in mammals is expensive and cannot be afforded in 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 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 known ERQC inhibitors 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 elf-18 but not to the flagellin-derived flag-22 peptide. In both NB-DNJ-treated and -untreated plants, the phenotype closely follows the one observed for the ER α-glucosidase II impaired plant, At psl5-1. Therefore, Arabidopsis thaliana is a promising platform for the development of low-cost proof-of-concept in vivo ERQC modulation.