Binding of Hepatitis C Virus Envelope Protein E2 to CD81 Up-regulates Matrix Metalloproteinase-2 in Human Hepatic Stellate Cells

Mazzocca, Antonio; Sciammetta, Silvia Cappadona; Carloni, Vinicio; Cosmi, Lorenzo; Annunziato, Francesco; Harada, Takashi; Abrignani, Sergio; Pinzani, Massimo

doi:10.1074/jbc.m410161200

Cited by 119 publications

(85 citation statements)

References 44 publications

(45 reference statements)

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“…Furthermore, CD81 is a required receptor for the hepatitis C virus (HCV) (Levy and Shoham, 2005), whose envelope proteins have been found to associate with CD81 in exosomes (Masciopinto et al, 2004). Similarly to our findings on TfR2, the binding of HCV envelope protein E2 to CD81 activates the phosphorylation of ERK1/ERK2 (Mazzocca et al, 2005). Interestingly, TfR2 expression is markedly increased in the liver of patients with chronic hepatitis C (Takeo et al, 2005).…”

Section: Discussionsupporting

confidence: 63%

TfR2 localizes in lipid raft domains and is released in exosomes to activate signal transduction along the MAPK pathway

Calzolari

Raggi

Deaglio

et al. 2006

Journal of Cell Science

176

130

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antibody or with human or bovine holotransferrin showed that it activated ERK1/ERK2 and p38 MAP kinases. Integrity of lipid rafts was required for MAPK activation. Co-localization of TfR2 with CD81, a raft tetraspanin exported through exosomes, prompted us to investigate exosomes released by HepG2 and K562 cells into culture medium. TfR2, CD81 and to a lesser extent caveolin-1, were found to be part of the exosomal budding vesicles. In conclusion, the present study indicates that TfR2 localizes in LDTI microdomains, where it promotes cell signalling, and is exported out of the cells through the exosome pathway, where it acts as an intercellular messenger.Key words: Transferrin, Iron metabolism, Lipid rafts, Cell signalling SummaryTfR2 localizes in lipid raft domains and is released in exosomes to activate signal transduction along the MAPK pathway

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Section: Discussionsupporting

confidence: 63%

TfR2 localizes in lipid raft domains and is released in exosomes to activate signal transduction along the MAPK pathway

Calzolari

Raggi

Deaglio

et al. 2006

Journal of Cell Science

176

130

View full text Add to dashboard Cite

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“…Moreover, expression of HCV nonstructural and core proteins induces stellate cell proliferation, release of inflammatory signals, 202 and CTGF, 203 although interaction of HCV E2 protein stimulates MMP-2 expression. 204 Furthermore, hepatocytes harboring replicating HCV in culture produce fibrogenic stimuli towards stellate cells. 205 In HCV-infected liver, chemokines promote lymphocyte recruitment.…”

Section: Hcv and Hivmentioning

confidence: 99%

Mechanisms of Hepatic Fibrogenesis

2008

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Substantial improvements in the treatment of chronic liver disease have accelerated interest in uncovering the mechanisms underlying hepatic fibrosis and its resolution. Activation of resident hepatic stellate cells into proliferative, contractile, and fibrogenic cells in liver injury remains a dominant theme driving the field. However, several new areas of rapid progress in the past 5-10 years also have taken root, including: (1) identification of different fibrogenic populations apart from resident stellate cells, for example, portal fibroblasts, fibrocytes, and bone-marrow-derived cells, as well as cells derived from epithelial mesenchymal transition; (2) emergence of stellate cells as finely regulated determinants of hepatic inflammation and immunity; (3) elucidation of multiple pathways controlling gene expression during stellate cell activation including transcriptional, posttranscriptional, and epigenetic mechanisms; (4) recognition of disease-specific pathways of fibrogenesis; (5) re-emergence of hepatic macrophages as determinants of matrix degradation in fibrosis resolution and the importance of matrix cross-linking and scar maturation in determining reversibility; and (6) hints that hepatic stellate cells may contribute to hepatic stem cell behavior, cancer, and regeneration. Clinical and translational implications of these advances have become clear, and have begun to impact significantly on the management and outlook of patients with chronic liver disease.The field of hepatic fibrosis is flourishing thanks to continued experimental advances complemented by exciting progress in the treatment of chronic liver disease. 1 Control of chronic hepatitis B and C by antiviral therapies has established that advanced fibrosis can regress in association with improved clinical outcomes, 2-4 thereby intensifying enthusiasm to uncover the mechanistic basis for hepatic fibrogenesis and its attenuation. At the same time, simple paradigms defining the cellular sources of extracellular matrix (ECM), and the roles of cytokines and paracrine interactions among resident liver cells and inflammatory cells have yielded a more nuanced understanding of how the liver responds to injury. These advances have had a collateral benefit towards understanding fibrosis in other organs, particularly the pancreas. 5 Thus, a review of the mechanisms underlying hepatic fibrosis is not only timely, but is more clinically relevant than ever. This article focuses on recent advances in the field, building on established principles from earlier reviews 6,7 while weaving in their clinical relevance, but also emphasizing the molecular subtleties that have emerged through continued progress in the field. General PrinciplesFibrosis, or scarring of the liver, is a wound-healing response that engages a range of cell types and mediators to encapsulate injury. Although even acute injury will activate mechanisms of fibrogenesis, the sustained signals associated with chronic liver disease caused by infection, Cirrhosis, the most advanced stage ...

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“…Furthermore, HCV envelop protein E2 induces matrix metallo-proteinase-2 in activated HSCs. 34 Thus, a direct interaction between HCV proteins and HSCs may contribute to HCV-induced liver fibrosis.…”

Section: A6 Hcv and Liver Fibrosismentioning

confidence: 99%

Mechanisms of alcohol-induced hepatic fibrosis: A summary of the Ron Thurman Symposium

2006

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Binding of Hepatitis C Virus Envelope Protein E2 to CD81 Up-regulates Matrix Metalloproteinase-2 in Human Hepatic Stellate Cells

Cited by 119 publications

References 44 publications

TfR2 localizes in lipid raft domains and is released in exosomes to activate signal transduction along the MAPK pathway

TfR2 localizes in lipid raft domains and is released in exosomes to activate signal transduction along the MAPK pathway

Mechanisms of Hepatic Fibrogenesis

Mechanisms of alcohol-induced hepatic fibrosis: A summary of the Ron Thurman Symposium

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