Positive feedback loop of YB-1 interacting with Smad2 promotes liver fibrosis.
Y-box binding protein (YB-1), known as a multifunctional cellular protein in various biological processes, was recently reported to be associated with liver fibrosis. The critical role of TGF-β/Smad signaling pathway in stimulating the transcription of fibrotic genes in fibroblasts have already been identified, however, whether and how YB-1 modulated liver fibrosis via TGF-β/Smad signaling pathway remains largely unknown. In our previous study, we proved that ectopic TGF-β was associated with YB-1 expression. Herein, by combining in vitro experiments in LX2 human hepatic stellate cells and in vivo studies by building CCl4 based mice liver fibrosis model, we showed that YB-1 and p-YB-1 were upregulated in liver fibrosis tissue, and YB-1 promoted the deposition of excess extracellular matrix. Mechanistically, Smad2, a key member in TGF-β signaling pathway, acted as a transcription factor that triggered YB-1 promoter, while on the other hand, p-YB-1 stabilized Smad2 by attenuating its ubiquitination. Knockdown of Smad2 could reduce YB-1 expression, which in turn shorter the half time of Smad2. Furthermore, the serine102 residue of YB-1 both affected its binding and stabilizing activity to Smad2. These finding demonstrated that YB-1 and Smad2 played as a positive feedback loop in promoting liver fibrosis. In conclusion, TGF-β signaling pathway may influence liver fibrosis by incorporating with YB-1, indicating that YB-1 could be a potential target for therapies against liver fibrosis.
Department of Digestive Diseases, Shanghai East Hospital, Tongji University, Shanghai 200120, PR China.
Panpan
P
Xiong
Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, PR China.
Jun
J
Zhang
Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, PR China.
Diannan
D
Xu
Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, PR China.
Jie
J
Zhu
Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, PR China.
Wenshuai
W
Li
Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, PR China. Electronic address: jieliu@fudan.edu.cn.
Jie
J
Liu
Department of Digestive Diseases, Shanghai East Hospital, Tongji University, Shanghai 200120, PR China. Electronic address: liufeiguo2010@163.com.
Fei
F
Liu
D000818:Animals; D002251:Carbon Tetrachloride; D002460:Cell Line; D025461:Feedback, Physiological; D057809:HEK293 Cells; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D054875:Ubiquitination
D002251:Carbon Tetrachloride; D051899:Smad2 Protein; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C497783:Smad2 protein, mouse; C541744:Ybx1 protein, mouse
Positive feedback loop; Smad2; TGF-β; Y-box binding protein (YB-1)