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Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy

Moran Dvela-Levitt1, Maria Kost-Alimova2, Maheswarareddy Emani1

  • 1Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Cell
|July 27, 2019
PubMed

Insights

A novel small molecule, BRD4780, clears toxic Mucin 1 kidney disease (MKD) protein aggregates by targeting the TMED9 receptor. This discovery offers a promising therapeutic strategy for MKD and other proteinopathies.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Biochemistry

Background:

  • Toxic proteinopathies result from intracellular misfolded protein accumulation, lacking targeted treatments.
  • Mucin 1 kidney disease (MKD) is caused by a MUC1 gene frameshift mutation (MUC1-fs), leading to toxic intracellular accumulation.
  • The ATF6 unfolded protein response (UPR) pathway is activated by MUC1-fs accumulation.

Purpose of the Study:

  • To identify therapeutic strategies for Mucin 1 kidney disease (MKD).
  • To investigate the mechanism of MUC1-fs intracellular accumulation and clearance.
  • To explore the role of cargo receptors in misfolded protein trafficking.

Main Methods:

  • Screening for small molecules that clear MUC1-fs.
  • Utilizing patient-derived cells, knockin mouse models, and kidney organoids.
  • Investigating the interaction between BRD4780, MUC1-fs, and the TMED9 cargo receptor.

Main Results:

  • BRD4780 effectively clears MUC1-fs from patient cells, mouse kidneys, and organoids.
  • MUC1-fs is sequestered in TMED9-containing vesicles within the early secretory pathway.
  • BRD4780 binds TMED9, releasing MUC1-fs for lysosomal degradation, mimicking TMED9 deletion effects.

Conclusions:

  • BRD4780 is a promising therapeutic lead for Mucin 1 kidney disease (MKD).
  • The study reveals a novel mechanism of misfolded protein entrapment by cargo receptors.
  • Targeting TMED9 offers a strategy for releasing and degrading misfolded proteins in toxic proteinopathies.
Keywords:
COP vesiclesER stressGolgi apparatuscargo receptorendoplasmic reticulumepithelial cellskidneyorganoidssecretory pathwayunfolded protein response

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