#AI Reads Urine# Disrupted uromodulin trafficking is rescued by targeting TMED cargo receptors
Published 18 December, 2024
The research paper was published in The Journal of Clinical Investigation on December 16, 2024. The major authors include Silvana Bazua-Valenti, Anna Greka, etc. They are affiliated with institutions such as The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Brigham and Women’s Hospital and Harvard Medical School.
Uromodulin (UMOD), the most abundant protein in human urine, is expressed in specific kidney tubule segments and regulates essential channels and co-transporters. Its trafficking, glycosylation, and urinary excretion are crucial for kidney health. Mutations in the UMOD gene cause autosomal dominant tubulointerstitial kidney disease (ADTKD-UMOD), leading to kidney failure. The misfolded mutant UMOD is trapped intracellularly, activating the unfolded protein response and ER-stress pathways, and potentially interfering with the normal trafficking of wild-type UMOD. The molecular machinery and interacting proteins involved in UMOD trafficking remain unclear, although previous studies have suggested a role for TMED cargo receptors in the trafficking of some proteins.
This study provides insights into the mechanisms regulating UMOD trafficking and the role of TMED cargo receptors in this process. The findings suggest that TMED-targeted small molecules could be a potential treatment strategy for ADTKD-UMOD, a currently incurable genetic disorder. The results also highlight the importance of understanding the complex regulation of protein trafficking in kidney health and disease and may inspire further research into the development of novel therapies for kidney proteinopathies.
The original publication link: https://www.jci.org/articles/view/180347
Youhe Gao
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