Newly made proteins which do not quite achieve the correct 3D shape in the ER are moved to the cell cytoplasm via a specific membrane pore, and broken down. Many disease causing gene mutations e.g. in cystic fibrosis, also result in misfolding of the mutant protein, and its transport though this pore, for cytoplasmic degradation. This pore is hijacked by some bacterial toxins which need to access the cytoplasm to induce pathology. We, in turn, have “hijacked” such toxins by an inactivation which retains their pore targetting, to generate a benign toxin which competes for the ER pore occupancy/translocation and thereby reduces degradation of misfolded proteins, including those whose loss cause genetic disease. Such toxins can, in part, restore normal function to reverse disease symptoms. This provides a new approach to the therapy of many inherent misfolding diseases.
Lingwood Lab discover new approach to rescue endogenous misfolded proteins