Ubiquitin Specific Protease USP48 Destabilizes NF-KB/p65 in Retinal Pigment Epithelium Cells

Activation of NF-?B transcription factor is strictly regulated to accurately direct cellular processes including inflammation, immunity, and cell survival. In the retina, the modulation of the NF-?B 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 (TNF?), leading to the activation of several transductional pathways, including NF-?B. However, the multiple factors orchestrating the appropriate regulation of NF-?B 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-?B/p65 in retinal pigment epithelium (RPE), at both basal conditions and following TNF? 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-?B transcriptional activity. These results delineate a novel role of USP48 in negatively regulating NF-?B in retinal cells, providing new opportunities for therapeutic intervention in retinal pathologies.