RACK1-mediated translation control promotes liver fibrogenesis

Liu, Min; Peng, Peike; Wang, Jiajun; Wang, Lan; Duan, Fangfang; Jia, Dongwei; Ruan, Yuanyuan; Gu, Jianxin

doi:10.1016/j.bbrc.2015.05.040

Cited by 11 publications

(6 citation statements)

References 27 publications

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“…Moreover, receptor for activated C-kinase 1 (RACK1), a scaffold protein involved in numerous cellular processes and signaling pathways, is another TGF-β downstream target involved in the HSC activation. RACK1 is able to induce pro-fibrogenic pathways in a TGF-β-dependent manner, contributing to differentiation, proliferation, and migration of HSC ( 92 , 93 ). Indeed, in this migratory phenotype and in remodeling of the cytoskeleton in TGF-β-activated HSC is also involved the role of Rho guanosine triphosphatase (Rho GTPase) signaling ( 94 ).…”

Section: Relevance Of Tgf-β and Hsc Differentiation During Liver Fibrmentioning

confidence: 99%

Transforming Growth Factor-β-Induced Cell Plasticity in Liver Fibrosis and Hepatocarcinogenesis

2018

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The Transforming Growth Factor-beta (TGF-β) family plays relevant roles in the regulation of different cellular processes that are essential for tissue and organ homeostasis. In the case of the liver, TGF-β signaling participates in different stages of disease progression, from initial liver injury toward fibrosis, cirrhosis and cancer. When a chronic injury takes place, mobilization of lymphocytes and other inflammatory cells occur, thus setting the stage for persistence of an inflammatory response. Macrophages produce profibrotic mediators, among them, TGF-β, which is responsible for activation -transdifferentiation- of quiescent hepatic stellate cells (HSC) to a myofibroblast (MFB) phenotype. MFBs are the principal source of extracellular matrix protein (ECM) accumulation and prominent mediators of fibrogenesis. TGF-β also mediates an epithelial-mesenchymal transition (EMT) process in hepatocytes that may contribute, directly or indirectly, to increase the MFB population. In hepatocarcinogenesis, TGF-β plays a dual role, behaving as a suppressor factor at early stages, but contributing to later tumor progression, once cells escape from its cytostatic effects. As part of its potential pro-tumorigenic actions, TGF-β induces EMT in liver tumor cells, which increases its pro-migratory and invasive potential. In parallel, TGF-β also induces changes in tumor cell plasticity, conferring properties of a migratory tumor initiating cell (TIC). The main aim of this review is to shed light about the pleiotropic actions of TGF-β that explain its effects on the different liver cell populations. The cross-talk with other signaling pathways that contribute to TGF-β effects, in particular the Epidermal Growth Factor Receptor (EGFR), will be presented. Finally, we will discuss the rationale for targeting the TGF-β pathway in liver pathologies.

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Section: Relevance Of Tgf-β and Hsc Differentiation During Liver Fibrmentioning

confidence: 99%

Transforming Growth Factor-β-Induced Cell Plasticity in Liver Fibrosis and Hepatocarcinogenesis

2018

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“…It is generally believed that eIF4E plays a central role in the initial stage of cap-dependent translation since its minimum content and is present in the cell in limiting molar amounts. 21,22 The combination of 4E-BP and eIF4E inhibited the formation of eIF4F. Low phosphorylated 4E-BP has a high affinity with eIF4E and can compete with eIF4G for the binding site of eIF4E, thus preventing the formation of eIF4F and the initiation of Figure 1 Functional domains in HIF-1α transcription factors.…”

Section: The Protein Structure and Regulation Of Hif-1α Hif-1α Proteimentioning

confidence: 99%

<p>HIF-1α is a Potential Molecular Target for Herbal Medicine to Treat Diseases</p>

Li¹,

He²,

Zhang³

et al. 2020

DDDT

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“…RACK1 is highly expressed in normal liver and has been implicated in the liver physiology and diseases. For example, it has been reported that RACK1 expression in hepatic stellate cells is positively correlated with the clinical stage of liver fibrosis 10 - 12 . RACK1 knockdown suppresses the expression of pro-fibrogenic factors in vitro and in vivo 10 - 12 , and stimulation of cap-dependent translation was proposed as the key underlying mechanism 12 .…”

Section: Introductionmentioning

confidence: 99%

“…For example, it has been reported that RACK1 expression in hepatic stellate cells is positively correlated with the clinical stage of liver fibrosis 10 - 12 . RACK1 knockdown suppresses the expression of pro-fibrogenic factors in vitro and in vivo 10 - 12 , and stimulation of cap-dependent translation was proposed as the key underlying mechanism 12 . Elevated RACK1 expression has also been detected in hepatocellular carcinoma cells and has been demonstrated to promote oncogenic growth 13 , 14 .…”

Section: Introductionmentioning

confidence: 99%

Hepatic RACK1 deficiency protects against fulminant hepatitis through myeloid-derived suppressor cells

Liu¹,

Wang²,

Deng³

et al. 2022

Theranostics

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Fulminant hepatitis (FH) is a life-threatening disease with partially understood pathogenesis. It has been demonstrated that myeloid-derived suppressor cells (MDSCs) are recruited into the liver during this process, and their augmented accumulation by various strategies protects against liver injury. However, the underlying mechanism(s) remain elusive. Receptor for activated C kinase 1 (RACK1), a multi-functional scaffold protein, is highly expressed in normal liver and has been implicated in liver physiology and diseases, but the in vivo role of hepatic RACK1 in FH remains unknown. Methods: Survival curves and liver damage were monitored to investigate the in vivo role of hepatic RACK1 in FH. The liver microenvironment was explored by microarray-based transcriptome analysis, flow cytometry, immunoblotting, and immunohistochemistry. MDSCs were identified with phenotypic and functional characteristics. Functional antibodies were used to target MDSCs. Co-culture techniques were used to study the underlying mechanism(s) of protection. The interaction of RACK1 with histone deacetylase 1 (HDAC1) and the consequent effects on HDAC1 ubiquitination were analyzed. Ectopic expression of HDAC1 with recombinant adeno-associated virus serotype 8 was conducted to confirm the role of HDAC1 in the protective effects of hepatic RACK1 deficiency against FH. Post-translational modifications of RACK1 were also investigated during the induction of FH. Results: Liver-specific RACK1 deficiency rendered mice resistant to FH. RACK1-deficient livers exhibited high basal levels of chemokine (C-X-C motif) ligand 1 (CXCL1) and S100 calcium-binding protein A9 (S100A9), associated with MDSC accumulation under steady-state conditions. Targeting MDSCs with an antibody against either Gr1 or DR5 abrogated the protective effects of liver-specific RACK1 deficiency. Accumulated MDSCs inhibited inflammatory cytokine production from macrophages and enhanced IκB kinase (IKK)/NF-κB pathway activation in hepatocytes. Further investigation revealed that RACK1 maintained HDAC1 protein level in hepatocytes by direct binding, thereby controlling histone H3K9 and H3K27 acetylation at the Cxcl1 and S100a9 promoters. Ectopic expression of HDAC1 in livers with RACK1 deficiency partially reversed the augmented Cxcl1/S100a9 → MDSCs → IKK/NF-κB axis. During FH induction, RACK1 was phosphorylated at serine 110, enhancing its binding to ubiquitin-conjugating enzyme E2T and promoting its ubiquitination and degradation. Conclusion: Liver-specific RACK1 deficiency protects against FH through accelerated HDAC1 degradation and the consequent CXCL1/S100A9 upregulation and MDSC accumulation.

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RACK1-mediated translation control promotes liver fibrogenesis

Cited by 11 publications

References 27 publications

Transforming Growth Factor-β-Induced Cell Plasticity in Liver Fibrosis and Hepatocarcinogenesis

Transforming Growth Factor-β-Induced Cell Plasticity in Liver Fibrosis and Hepatocarcinogenesis

<p>HIF-1α is a Potential Molecular Target for Herbal Medicine to Treat Diseases</p>

Hepatic RACK1 deficiency protects against fulminant hepatitis through myeloid-derived suppressor cells

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