ERQC modulation for broad-spectrum glycoprotein secretion-rescue in rare disease
A wonderfully efficient protein folding machinery in the Endoplasmic Reticulum (ER) of eukaryotic cells ensures that only correctly folded glycoproteins can exit the ER and proceed to the Golgi, and from the Golgi continue along the secretory pathway towards their individual cellular or extracellular destinations.
The stringency of Endoplasmic Reticulum Quality Control (ERQC) – while of great advantage to healthy cells – can originate severe disease in patients carrying mutant glycoproteins: the latter are detected as incorrectly folded, and either retained in the ER or degraded by ER-associated degradation (ERAD). The zeal of the otherwise excellent ERQC machinery bears particularly unfortunate consequences when the mutation affecting the glycoprotein is mild, i.e. it impairs but does not abrogate its function (“responsive mutant”). In these cases, ERQC blocks mutated competent glycoprotein secretion - and disease ensues.
We postulate that in rare disease patients carrying responsive glycoprotein mutants, small molecule modulators of ERQC would rescue the secretion and residual activity of slightly misfolded and yet still active glycoproteins, thus alleviating pathogenic symptoms. The fraction of responsive patients who could derive therapeutic benefit from ERQC modulation therapy depends on the disease, and varies between 70% in cystic fibrosis patients to 15-50% in lysosomal storage diseases.
In order to develop and test ERQC partial inhibitors as broad-spectrum rescuers of secretion for responsive mutant glycoproteins, we investigate the molecular mechanisms by which the eukaryotic cell either retains misfolded glycoproteins in the ER and/or degrades them by ERAD. Cryo-EM and X-ray crystallography of recombinantly expressed purified ERQC proteins and their complexes with misfolded substrates are used to generate a range of biochemical and biological hypotheses, then tested by in vitro and in cellular assays, and in vivo experiments using the plant as a model organism.
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Andrea Lia, Gábor Tax