Department of Genetics, Microbiology and Statistics, Universitat de Barcelona, Avda. Diagonal 643, 08028 Barcelona, Spain.
CIBERER, Instituto de Salud Carlos III, 28029 Madrid, Spain.
Int J Mol Sci. 2022 Aug 26;23(17):9682. doi: 10.3390/ijms23179682.
Activation of NF-κB transcription factor is strictly regulated to accurately direct cellular processes including inflammation, immunity, and cell survival. In the retina, the modulation of the NF-κB pathway is essential to prevent excessive inflammatory responses, which plays a pivotal role in many retinal neurodegenerative diseases, such as age-related macular degeneration (AMD), diabetic retinopathy (DR), and inherited retinal dystrophies (IRDs). A critical cytokine mediating inflammatory responses in retinal cells is tumor necrosis factor-alpha (TNFα), leading to the activation of several transductional pathways, including NF-κB. However, the multiple factors orchestrating the appropriate regulation of NF-κB in retinal cells still remain unclear. The present study explores how the ubiquitin-specific protease 48 (USP48) downregulation impacts the stability and transcriptional activity of NF-κB/p65 in retinal pigment epithelium (RPE), at both basal conditions and following TNFα stimulation. We described that USP48 downregulation stabilizes p65. Notably, the accumulation of p65 is mainly detectable in the nuclear compartment and it is accompanied by an increased NF-κB transcriptional activity. These results delineate a novel role of USP48 in negatively regulating NF-κB in retinal cells, providing new opportunities for therapeutic intervention in retinal pathologies.
NF-κB 转录因子的激活受到严格调控，以准确指导包括炎症、免疫和细胞存活在内的细胞过程。在视网膜中，NF-κB 途径的调节对于防止过度炎症反应至关重要，过度炎症反应在许多视网膜神经退行性疾病中起关键作用，如年龄相关性黄斑变性（AMD）、糖尿病性视网膜病变（DR）和遗传性视网膜营养不良（IRDs）。一种介导视网膜细胞炎症反应的关键细胞因子是肿瘤坏死因子-α（TNFα），它导致包括 NF-κB 在内的几个信号转导途径的激活。然而，协调视网膜细胞中 NF-κB 适当调节的多种因素仍不清楚。本研究探讨了泛素特异性蛋白酶 48（USP48）下调如何影响视网膜色素上皮（RPE）中 NF-κB/p65 的稳定性和转录活性，包括在基础条件和 TNFα 刺激下。我们描述了 USP48 下调稳定了 p65。值得注意的是，p65 的积累主要可检测到核区，并且伴随着 NF-κB 转录活性的增加。这些结果描绘了 USP48 在负向调节视网膜细胞中 NF-κB 方面的新作用，为视网膜病理学的治疗干预提供了新的机会。
