Fashemi Bisiayo E, Rougeau Amala K, Salazar Arnold M, Bark Steven J, Chappidi Rayvanth, Brown Jeffrey W, Cho Charles J, Mills Jason C, Mysorekar Indira U
Department of Obstetrics and Gynecology, Center for Reproductive Health Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
iScience. 2024 Oct 28;27(12):111282. doi: 10.1016/j.isci.2024.111282. eCollection 2024 Dec 20.
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 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. -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.
应激状态下膀胱尿路上皮内环境稳定的维持及快速再生对膀胱功能至关重要。在此，我们在小鼠模型中确定了IFRD1在维持尿路上皮内环境稳定方面的关键作用。我们证明，在稳态下，小鼠膀胱表达IFRD1，尤其是在尿路上皮中，其缺失会改变整体转录组，导致内溶酶体大量积累以及尿膜蛋白表达模式失调。我们表明，IFRD1在人尿路上皮细胞中与mRNA翻译调节因子相互作用。其缺失会导致蛋白稳态破坏、内质网应激（ER应激）增强，未折叠蛋白反应途径的PERK分支被激活，以及氧化应激增加。IFRD1缺陷的膀胱表现出尿路上皮细胞凋亡/脱落、基底细胞增殖增强、向表层细胞的分化减少、尿路上皮通透性增加以及排尿行为异常。这些发现突出了IFRD1在尿路上皮内环境稳定中的关键作用，表明其作为膀胱功能障碍治疗靶点的潜力。
