Y-box Protein-1 Is the Crucial Mediator of Antifibrotic Interferon-γ Effects

• Published in: The Journal of biological chemistry Vol. 281; no. 3; pp. 1784 - 1795
• Main Authors: Dooley, Steven, Said, Harun M., Gressner, Axel M., Floege, Jürgen, En-Nia, Abdelaziz, Mertens, Peter R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.01.2006
• Subjects: Animals; Carbon Tetrachloride Poisoning; Cell Line; Collagen - genetics; Fibrosis - prevention & control; Gene Expression Regulation - drug effects; Interferon-gamma - adverse effects; Interferon-gamma - drug effects; Liver Cirrhosis, Experimental - prevention & control; Rats; Signal Transduction; Smad7 Protein - genetics; Transforming Growth Factor beta - pharmacology; Y-Box-Binding Protein 1 - genetics; Y-Box-Binding Protein 1 - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M510215200

Y-box protein-1 (YB-1) is a known negative regulator of collagen (Col) expression by two different mechanisms, acting directly through binding to an interferon-γ response element within the col1A2 promoter and/or by physically interacting with p300/Smad3, thereby abrogating the stimulatory effect of transforming growth factor-β (TGF-β). Here, we report that YB-1 activation via the Jak1 signaling pathway is required and sufficient to confer interferon-γ-dependent activation of the smad7 gene. By binding to a bona fide recognition site within the smad7 promoter, YB-1 up-regulates smad7 transcription, which was additively enhanced by autoinhibitory TGF-β signaling. Importantly, the anti-TGF-β effect was not only supplied by induced Smad7 expression but was recapitulated in the context of the col1A2 promoter, where YB-1 overexpression abolished the trans-stimulatory TGF-β effect in a dominant fashion. In conclusion, YB-1 is the main target of interferon-γ signaling via Jak1 that exerts antifibrotic action by both interference with TGF-β signaling and direct down-regulation of collagen expression.