Progress Update: Defining the role of post-translational modification on FSHD protein DUX4

Update by Jocelyn O Eidahl PhD.

After a protein is made it can be decorated with certain chemical modifications which are displayed on the protein surface. We refer to these modifications as post-translational modifications or PTMs. PTMs can alter the protein’s ability to move within a cell, interact with other proteins or DNA, or increase the lifetime of that particular protein, among several other roles. Importantly, PTMs can have a profound role in disease and are being pursued as targets in therapies for a wide-variety of diseases including cancer, autoimmune diseases, cardiovascular disease, kidney disease and age-related disease.

Our lab’s goal was to first determine if the DUX4 protein could be decorated with PTMs, and then to determine if adding or removing these modifications could make the protein more or less toxic. In the first year of funding, we did indeed find that DUX4 protein can be modified by several different classes of PTMs. We designed a strategy to add and remove these from the DUX4 protein and found that two classes in particular could alter DUX4 toxicity in cell culture. We examined the effects of adding/removing these modifications on toxicity, movement in the cells, lifetime of the protein, induction of FSHD disease biomarkers and promoting DNA damage in human cells. In addition, we identified a group of modifying enzymes that could interact with DUX4 to add or remove these PTMs, and began screening the effectiveness of inhibitors targeting some of these enzymes to reduce DUX4 toxicity in cell culture. Importantly, we have identified three lead compounds which target the same modification class.

During the second year of funding, we are continuing to screen these modifying enzyme inhibitors in FSHD muscle cells in order to understand their ability to prevent the damaging effects of DUX4. Ultimately, we hope this work will help establish a framework for altering the DUX4 protein for FSHD therapeutics.

See grant Defining the role of post-translational modification on FSHD protein DUX4