Pietro Roversi

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

Pietro Roversi 2.0

Research Summary

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 cellula assays, and in vivo experiments using the plant as a model organism.

ERQC and ERAD machineries in the eukaryotic cell. Adapted from Molecular Biology of the Cell (© Garland Science 2008)
ERQC and ERAD machineries in the eukaryotic cell. Adapted from Molecular Biology of the Cell (© Garland Science 2008)

Four distinct crystal structures of UGGT (the 170 kDa ERQC checkpoint enzyme) trap the enzyme in as many different conformations. The UGGT conformations are likened to settings of an adjustable wrench, enabling recognition of nuts of distinct sizes - the latter symbolising different misfolded UGGT glycoprotein clients
Four distinct crystal structures of UGGT (the 170 KDa ERQC checkpoint enzyme) trap the enzyme
in as many different conformations. The UGGT conformations are likened to settings of an adjustable wrench,
enabling recognition of nuts of distinct sizes - the latter symbolising different misfolded UGGT glycoprotein clients

Key Publications

Group Members:

Andrea Lia

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