Pietro Roversi

ERQC/ERAD modulation for broad-spectrum glycoprotein secretion-rescue in rare disease

ERQC glycoprotein misfolding golgi rare diseasesResearch summary

Wonderfully efficient protein folding surveillance machineries in the Endoplasmic Reticulum (ER) of eukaryotic cells ensure 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: ER Quality Control (ERQC) helps glycoproteins to fold and retains them in the ER until they are ready to leave; ER Associated Degradation (ERAD) dispatches any hopelessly misfolded glycoproteins to a cytoplasmic shredder (see Figure).

The stringency of ERQC and ERAD – while of great advantage to healthy cells – can originate severe disease in patients carrying mutant glycoproteins: the latter are detected as incorrectly folded, retained in the ER and eventually degraded. ERQC/ERAD zeal 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, secretion of the mutated competent glycoprotein never takes place - and disease ensues.

We postulate that in rare disease patients carrying responsive glycoprotein mutants, small molecule modulators of ERQC/ERAD 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/ERAD 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/ERAD partial inhibitors as broad-spectrum rescuers of secretion for responsive mutant glycoproteins, we investigate the molecular mechanisms by which the eukaryotic cell eitherERQC retains misfolded glycoproteins in the ER and/or how ERAD degrades them by ERAD. Cryo-EM and X-ray crystallography of recombinantly expressed purified ERQC/ERAD 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.

Pietro’s experiments are discussed in the Open Secretion Rescue blog at SGC Toronto

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Gábor Tax