IFRD1 is required for maintenance of bladder epithelial homeostasis
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
Affiliations
Bisiayo E. Fashemi
Department of Obstetrics and Gynecology, Center for Reproductive Health Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA
Amala K. Rougeau
Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA
Arnold M. Salazar
Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA
Steven J. Bark
Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA; Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA
Rayvanth Chappidi
Department of Obstetrics and Gynecology, Center for Reproductive Health Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA
Jeffrey W. Brown
Department of Medicine, Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO 63110, USA
Charles J. Cho
Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA
Jason C. Mills
Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA; Corresponding author
Indira U. Mysorekar
Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA; Department of Molecular Virology and Microbiology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA; Huffington Center on Aging, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA; Corresponding author
Summary: 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.
