Esther Elonga

All Publications

• Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy CELL Dvela-Levitt, M., Kost-Alimova, M., Emani, M., Kohnert, E., Thompson, R., Sidhom, E., Rivadeneira, A., Sahakian, N., Roignot, J., Papagregoriou, G., Montesinos, M. S., Clark, A. R., McKinney, D., Gutierrez, J., Roth, M., Ronco, L., Elonga, E., Carter, T. A., Gnirke, A., Melanson, M., Hartland, K., Wieder, N., Hsu, J., Deltas, C., Hughey, R., Bleyer, A. J., Kmoch, S., Zivna, M., Baresova, V., Kota, S., Schlondorff, J., Heiman, M., Alper, S. L., Wagner, F., Weinsz, A., Golub, T. R., Landeri, E. S., Greka, A. 2019; 178 (3): 521-+

  Abstract

  Intracellular accumulation of misfolded proteins causes toxic proteinopathies, diseases without targeted therapies. Mucin 1 kidney disease (MKD) results from a frameshift mutation in the MUC1 gene (MUC1-fs). Here, we show that MKD is a toxic proteinopathy. Intracellular MUC1-fs accumulation activated the ATF6 unfolded protein response (UPR) branch. We identified BRD4780, a small molecule that clears MUC1-fs from patient cells, from kidneys of knockin mice and from patient kidney organoids. MUC1-fs is trapped in TMED9 cargo receptor-containing vesicles of the early secretory pathway. BRD4780 binds TMED9, releases MUC1-fs, and re-routes it for lysosomal degradation, an effect phenocopied by TMED9 deletion. Our findings reveal BRD4780 as a promising lead for the treatment of MKD and other toxic proteinopathies. Generally, we elucidate a novel mechanism for the entrapment of misfolded proteins by cargo receptors and a strategy for their release and anterograde trafficking to the lysosome.

  View details for DOI 10.1016/j.cell.2019.07.002

  View details for Web of Science ID 000476973800005

  View details for PubMedID 31348885