Smurf2, an E3 ubiquitin ligase, interacts with PDE4B and attenuates liver fibrosis through miR-132 mediated CTGF inhibition

Yu Cai; Guanqun Huang; Lijie Ma; Ling Dong; She Chen; Xizhong Shen; Shuncai Zhang; Ruyi Xue; Deqiang Sun; Si Zhang

doi:10.1016/j.bbamcr.2017.10.011

Smurf2, an E3 ubiquitin ligase, interacts with PDE4B and attenuates liver fibrosis through miR-132 mediated CTGF inhibition

Biochim Biophys Acta Mol Cell Res. 2018 Feb;1865(2):297-308. doi: 10.1016/j.bbamcr.2017.10.011. Epub 2017 Oct 31.

Authors

Yu Cai¹, Guanqun Huang², Lijie Ma³, Ling Dong¹, She Chen⁴, Xizhong Shen¹, Shuncai Zhang¹, Ruyi Xue⁵, Deqiang Sun⁶, Si Zhang⁷

Affiliations

¹ Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai, China.
² The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong Province, China.
³ Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
⁴ Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai, China.
⁵ Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai, China. Electronic address: xue.ruyi@zs-hospital.sh.cn.
⁶ Institute of Biosciences & Technology, College of Medicine, Texas A&M University, Houston, TX, USA. Electronic address: dsun@tamu.edu.
⁷ Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address: zhangsi@fudan.edu.cn.

PMID: 29100790
DOI: 10.1016/j.bbamcr.2017.10.011

Abstract

We previously reported that Smad ubiquitin regulatory factor 2 (Smurf2) activity was decreased in human fibrotic livers. Here, we overexpressed Smurf2 in livers of transgenic mice and observed inhibited collagen deposition and hepatic stellate cell activation in fibrotic model induced by carbon tetrachloride treatment or bile duct ligation. Hepatic Smurf2 overexpression also inhibited the production of connective tissue growth factor (CTGF), a central mediator of liver fibrosis. Using miRNA array and bioinformatics analyses, we identified miR-132 as a mediator of this inhibitory effect. miR-132 directly targets the 3'-untranslated region of CTGF and was transcriptionally upregulated by cAMP-PKA-CREB signaling. In addition, Smurf2 activated cAMP-PKA-CREB pathway by interacting with phosphodiesterase 4B (PDE4B) and facilitating its degradation. Thus, we have demonstrated a previously unrecognized anti-fibrotic pathway controlled by Smurf2.

Keywords: Phosphodiesterase; Smurf2; Ubiquitination; cAMP; miR-132.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Connective Tissue Growth Factor / genetics
Connective Tissue Growth Factor / metabolism*
Cyclic Nucleotide Phosphodiesterases, Type 4 / genetics
Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
Female
Humans
Liver Cirrhosis / genetics
Liver Cirrhosis / metabolism*
Liver Cirrhosis / pathology
Male
Mice
MicroRNAs / genetics
MicroRNAs / metabolism*
Oligonucleotide Array Sequence Analysis
Signal Transduction*
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*

Substances

CCN2 protein, human
MIRN132 microRNA, human
MicroRNAs
Connective Tissue Growth Factor
SMURF2 protein, human
Ubiquitin-Protein Ligases
Cyclic Nucleotide Phosphodiesterases, Type 4
PDE4B protein, human