Abstract: TH-PO0138
Transmembrane Emp24 Protein Transport Domain-Containing (TMED) Entrapment Complex Is a Therapeutic Node for Mucin 1 Kidney Disease and Other Proteinopathies
Session Information
- Integrative Genomics and Multi-Omics in Noncystic Genetic Kidney Disease
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)
Authors
- Riedl Khursigara, Magdalena, Broad Institute, Cambridge, Massachusetts, United States
- Goss, Alissa, Broad Institute, Cambridge, Massachusetts, United States
- De Mata, Christine Danielle Aquino, Broad Institute, Cambridge, Massachusetts, United States
- Muraleedharan, Ranjithmenon, Broad Institute, Cambridge, Massachusetts, United States
- Brown, Matthew, Broad Institute, Cambridge, Massachusetts, United States
- Keller, Keith H., Broad Institute, Cambridge, Massachusetts, United States
- Collantes, Edward Ryan, Broad Institute, Cambridge, Massachusetts, United States
- Kwon, Seulki, Broad Institute, Cambridge, Massachusetts, United States
- Alimova, Maria, Broad Institute, Cambridge, Massachusetts, United States
- Iqbal, Sumaiya, Broad Institute, Cambridge, Massachusetts, United States
- Pablo, Juan Lorenzo B., Broad Institute, Cambridge, Massachusetts, United States
- Greka, Anna, Broad Institute, Cambridge, Massachusetts, United States
Background
Mucin 1 kidney disease (MKD) is a form of Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) resulting in kidney failure. MKD is characterized by the toxic accumulation of mucin 1 owing to a frameshift mutation in the MUC1 gene (MUC1-fs). MUC1-fs misfolds and subsequently gets sequestered in organelles such as the Golgi compartment by TMEDs, a family of cargo receptors. With this study, we sought to elucidate the TMED proteins responsible for the toxic accumulation of MUC1-fs and their potential for therapeutic targeting.
Methods
We analyzed MUC1-fs expressing cells via optical pooled screening, and detailed biochemical and cell biological experiments. We then confirmed the functional relevance of our findings in mouse models of disease.
Results
Depletion of TMEDs 2,7,9 and 10 reduced MUC1-fs accumulation and together constituted a TMED entrapment complex. While TMEDs 2, 9 and 10 were broadly required for the stability of the complex, TMED7 seemed to be specific to the entrapment of MUC1-fs in the Golgi. In an unbiased search for the molecular partners of TMED7, we identified the integral Golgi protein GRASP55, as an anchor for TMED7-mediated MUC1-fs entrapment. Indeed, knock-out of GRASP55 reduced MUC1-fs and decreased Golgi localization of the TMED entrapment complex. With structure-guided site-directed mutagenesis experiments, we validated the binding of GRASP55 to the cytoplasmic tail of TMED7.
For therapeutic proof-of-concept, we developed BRD7635, a potent small molecule that disrupts the TMED entrapment complex. BRD7635 treatment abrogated MUC1-fs accumulation in patient derived cells in vitro, as well as in a knock-in mouse carrying a human MUC1-fs allele in vivo. TMED targeting also showed therapeutic potential in other proteinopathies such as retinitis pigmentosa. The accumulation of misfolded semaphorin 4A (F350C) and rhodopsin (P23H) could be decreased through depletion of TMED7. Functional testing in a rhodopsin P23H mouse showed improved vision after treatment with BRD7635.
Conclusion
We have identified the TMED7/2/9/10 complex as being responsible for the entrapment of several misfolded proteins. BRD7635 disrupts the entrapment complex, leading to improved outcomes in multiple diseases. We thus establish a new "nodal" therapeutic strategy for many genetically and clinically distinct proteinopathies.
Funding
- NIDDK Support