title: RACK1-mediated translation control promotes liver fibrogenesis.
abstract: Activation of quiescent hepatic stellate cells (HSCs) is the central event of liver fibrosis. The translational machinery is an optimized molecular network that affects cellular homoeostasis and diseases, whereas the role of protein translation in HSCs activation and liver fibrosis is little defined. Our previous report suggests that up-regulation of receptor for activated C-kinase 1(RACK1) in HSCs is critical for liver fibrogenesis. In this study, we found that RACK1 promoted macrophage conditioned medium (MCM)-induced assembly of eIF4F and phosphorylation of eIF4E in primary HSCs. RACK1 enhanced the translation and expression of pro-fibrogenic factors collagen 1α1, snail and cyclin E1 induced by MCM. Administration of PP242 or knock-down of eIF4E suppressed RACK1-stimulated collagen 1α1 production, proliferation and migration in primary HSCs. In addition, depletion of eIF4E attenuated thioacetamide (TAA)-induced liver fibrosis in vivo. Our data suggest that RACK1-mediated stimulation of cap-dependent translation plays crucial roles in HSCs activation and liver fibrogenesis, and targeting translation initiation could be a promising strategy for the treatment of liver fibrosis.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Peike
authors.initials: P
authors.lastname: Peng
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Biomedical Science, Fudan University, Shanghai 200032, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Biomedical Science, Fudan University, Shanghai 200032, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Duan
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Electronic address: jiadongwei@fudan.edu.cn.
authors.forename: Dongwei
authors.initials: D
authors.lastname: Jia
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Electronic address: yuanyuanruan@fudan.edu.cn.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Ruan
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Institute of Biomedical Science, Fudan University, Shanghai 200032, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Gu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics; D019927:Cyclin E / Q000235:genetics; D015536:Down-Regulation; D039562:Eukaryotic Initiation Factor-4F / Q000235:genetics / Q000378:metabolism*; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology*; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008807:Mice, Inbred BALB C; D009479:Neuropeptides / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D014176:Protein Biosynthesis; D000075370:Receptors for Activated C Kinase; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D019927:Cyclin E; D039562:Eukaryotic Initiation Factor-4F; D009479:Neuropeptides; D016376:Oligonucleotides, Antisense; D015513:Oncogene Proteins; C090294:RACK1 protein, mouse; D000075370:Receptors for Activated C Kinase; C568314:cyclin E1, mouse; D058570:TOR Serine-Threonine Kinases
keywords: Hepatic stellate cells; Liver fibrosis; RACK1; eIF4E