IFRD1 Is Required for Maintenance of Bladder Epithelial Homeostasis

Authors

Bisiayo E Fashemi
Amala K Rougeau
Arnold M Salazar
Steven J Bark
Rayvanth Chappidi
Jeffrey W Brown
Charles J Cho
Jason C Mills
Indira U Mysorekar

Publication Date

12-20-2024

Journal

iScience

DOI

10.1016/j.isci.2024.111282

PMID

39628564

PMCID

PMC11613175

PubMedCentral® Posted Date

10-28-2024

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Physiology, Cell biology, Transcriptomics

Abstract

The maintenance of homeostasis and rapid regeneration of the urothelium following stress are critical for bladder function. Here, we identify a key role for IFRD1 in maintaining urothelial homeostasis in a mouse model. We demonstrate that the murine bladder expresses IFRD1 at homeostasis, particularly in the urothelium, and its loss alters the global transcriptome with significant accumulation of endolysosomes and dysregulated uroplakin expression pattern. We show that IFRD1 interacts with mRNA-translation-regulating factors in human urothelial cells. Loss of Ifrd1 leads to disrupted proteostasis, enhanced endoplasmic reticulum (ER stress) with activation of the PERK arm of the unfolded protein response pathway, and increased oxidative stress. Ifrd1-deficient bladders exhibit urothelial cell apoptosis/exfoliation, enhanced basal cell proliferation, reduced differentiation into superficial cells, increased urothelial permeability, and aberrant voiding behavior. These findings highlight a crucial role for IFRD1 in urothelial homeostasis, suggesting its potential as a therapeutic target for bladder dysfunction.

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