Binding of hepatitis C virus envelope protein E2 to CD81 up-regulates matrix metalloproteinase-2 in human hepatic stellate cells

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

Research output: Contribution to journalArticle

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Abstract

The hepatitis C virus (HCV) envelope E2 glycoprotein is a key molecule regulating the interaction of HCV with cell surface proteins. E2 binds the major extracellular loop of human CD81, a tetraspanin expressed on various cell types including hepatocytes and B lymphocytes. Regardless, information on the biological functions originating from this interaction are largely unknown. Since human hepatic stellate cells (HSC) express high levels of CD81 at the cell surface, we investigated the E2/CD81 interaction in human HSC and the possible effects arising from this interaction. Matrix metalloproteinase-2 (MMP-2; gelatinase A), a major enzyme involved in the degradation of normal hepatic extracellular matrix, was up-regulated following the interaction between E2 and CD81. In particular, by employing zymography and Western blot, we observed that E2 binding to CD81 induces a time-dependent increase in the synthesis and activity of MMP-2. This effect was abolished by preincubating HSC with an anti-CD81 neutralizing antibody. Similar effects were detected in NIH3T3 mouse fibroblasts transfected with human CD81 with identical time course features. In addition, E2/CD81 interaction in human HSC induced the up-regulation of MMP-2 by increasing activator protein-2/DNA binding activity via ERK/MAPK phosphorylation. Finally, suppression of CD81 by RNA interference in human HSC abolished the described effects of E2 on these cells, indicating that CD81 is essential for the activation of the signaling pathway leading to the up-regulation of MMP-2. These results suggest that HSC may represent a potential target for HCV. The interaction of HCV envelope with CD81 on the surface of human HSC induces an increased expression of MMP-2. Increased degradation of the normal hepatic extracellular matrix in areas where HCV is concentrated may favor inflammatory infiltration and further parenchymal damage.

Original languageEnglish
Pages (from-to)11329-11339
Number of pages11
JournalJournal of Biological Chemistry
Volume280
Issue number12
DOIs
Publication statusPublished - Mar 25 2005

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Viral Envelope Proteins
Hepatic Stellate Cells
Matrix Metalloproteinase 2
Hepacivirus
Up-Regulation
Matrix Metalloproteinases
Viruses
Extracellular Matrix
Degradation
Phosphorylation
Lymphocytes
Liver
DNA-Binding Proteins
Fibroblasts
RNA Interference
human MMP2 protein
Neutralizing Antibodies
Infiltration
Hepatocytes
Glycoproteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

Mazzocca, A., Sciammetta, S. C., Carloni, V., Cosmi, L., Annunziato, F., Harada, T., ... Pinzani, M. (2005). Binding of hepatitis C virus envelope protein E2 to CD81 up-regulates matrix metalloproteinase-2 in human hepatic stellate cells. Journal of Biological Chemistry, 280(12), 11329-11339. https://doi.org/10.1074/jbc.M410161200

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.

In: Journal of Biological Chemistry, Vol. 280, No. 12, 25.03.2005, p. 11329-11339.

Research output: Contribution to journalArticle

Mazzocca, A, Sciammetta, SC, Carloni, V, Cosmi, L, Annunziato, F, Harada, T, Abrignani, S & Pinzani, M 2005, 'Binding of hepatitis C virus envelope protein E2 to CD81 up-regulates matrix metalloproteinase-2 in human hepatic stellate cells', Journal of Biological Chemistry, vol. 280, no. 12, pp. 11329-11339. https://doi.org/10.1074/jbc.M410161200
Mazzocca, Antonio ; Sciammetta, Silvia Cappadona ; Carloni, Vinicio ; Cosmi, Lorenzo ; Annunziato, Francesco ; Harada, Takashi ; Abrignani, Sergio ; Pinzani, Massimo. / Binding of hepatitis C virus envelope protein E2 to CD81 up-regulates matrix metalloproteinase-2 in human hepatic stellate cells. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 12. pp. 11329-11339.
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AU - Cosmi, Lorenzo

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