Chemical Strike against a Dominant-Inherited MUC1-Frameshifted Protein Associated with Progressive Kidney Disease

Abstract

In a recent paper by Dvela-Levitt et al., chemical screening using an immunofluorescent assay identified a compound that caused removal of a dominant-inherited misfolded secretory protein, mucin1-frameshifted, from an intracellular location in immortalized renal epithelial cells of a patient affected with progressive medullary cystic kidney disease. This illustrates the power of chemical screening at the cellular level to address specific proteinopathies and the utility of such compounds to illuminate novel cellular pathways that can clear toxic proteins.

Figure 1.. Accretion of Frameshifted Secretory Protein MUC1-fs Inside Renal Epithelial Cells in MUC1 Kidney Disease, Within the Early Secretory Pathway, and Removal by Treatment with a Small Molecule BRD4780.

(A) Model of trafficking of MUC1-fs in disease (top panel) and upon treatment with the small molecule BRD4780 (lower panel). (B) Immunoblotting of immortalized renal epithelial cells from a patient, with anti-MUC1-fs antibodies, in a basal state (−) and after BRD4780 treatment (+). Brefeldin A inhibits vesicular transport between the ER and Golgi. See text for detail. In the schematics, MUC1-fs is transported into the ER as a monomer but is thought to misfold and aggregate. The aggregated form appears to be blocked from ERAD and exits the ER, possibly in COP-II vesicles. A portion of this material is ultimately trafficked to the lysosome and degraded there, as indicated by Balifomycin A treatment (gray arrows in panels of A and compare lanes 1 and 5 in panel B), but another portion is ‘stuck’ in the ER–Golgi pathway and was found to colocalize with the p24α cargo receptor TMED9, enriched in COP-I vesicles. It is speculated that BRD4780 binds to the cytosolic tail of TMED9, associated with release from COP-I, allowing forward trafficking to the lysosome where MUC1-fs is turned over. Adapted from Dvela-Levitt et al. [2]. Abbreviations: BFA, Brefeldin A; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum-associated degradation; PM, plasma membrane.