Involvement of E3 ubiquitin ligase NEDD4-mediated YY1 ubiquitination in alleviating idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic and lethal lung disease characterized by progressive lung scarring. This study aims to elucidate the role of the E3 ubiquitin ligase NEDD4 in the ubiquitination of YY1 and its subsequent impact on TAB1 transcription, revealing a possible molecular mechanism in the development of IPF. Through bioinformatics analysis and both in vitro and in vivo experiments, we observed differential expression levels of NEDD4 and YY1 between normal and IPF samples, identifying NEDD4 as an upstream E3 ubiquitin ligase of YY1. Furthermore, binding sites for the transcription factor YY1 on the promoter region of TAB1 were discovered, indicating a direct interaction. In vitro experiments using HEPF cells showed that NEDD4 mediates the ubiquitination and degradation of YY1, leading to suppressed TAB1 transcription, thereby inhibiting cell proliferation and fibrogenesis. These findings were corroborated by in vivo experiments in an IPF mouse model, where the ubiquitination pathway facilitated by NEDD4 attenuated IPF progression through the downregulation of YY1 and TAB1 transcription. These results suggest that NEDD4 plays a crucial role in the development of IPF by modulating YY1 ubiquitination and TAB1 transcription, providing new insights into potential therapeutic targets for treating IPF.