Hepatitis C Virus Is Primed by CD81 Protein for Low pH-dependent Fusion
| Autor: | Arash Grakoui, Marlène Dreux, Nishi R. Sharma, Gregory B. Melikyan, Guaniri Mateu, François-Loïc Cosset |
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| Přispěvatelé: | Emory University [Atlanta, GA], IFR128, Virologie humaine, École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM) |
| Rok vydání: | 2011 |
| Předmět: |
Protein Conformation
Endosome Viral protein Recombinant Fusion Proteins Endocytic cycle Hepacivirus Buffers Biology Endocytosis medicine.disease_cause Microbiology Biochemistry Cell Line Tetraspanin 28 Cell membrane Viral Proteins 03 medical and health sciences [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases Antigens CD Viral entry medicine Humans Molecular Biology 030304 developmental biology 0303 health sciences Cell-Free System Cell Membrane 030302 biochemistry & molecular biology Antibodies Monoclonal Lipid bilayer fusion [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology Cell Biology Hydrogen-Ion Concentration Fusion protein Molecular biology 3. Good health Kinetics medicine.anatomical_structure [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology Liposomes |
| Zdroj: | Journal of Biological Chemistry Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2011, 286 (35), pp.30361-30376. ⟨10.1074/jbc.M111.263350⟩ Journal of Biological Chemistry, 2011, 286 (35), pp.30361-30376. ⟨10.1074/jbc.M111.263350⟩ |
| ISSN: | 0021-9258 1083-351X |
| Popis: | International audience; Hepatitis C virus (HCV) entry into permissive cells is a complex process that involves interactions with at least four co-factors followed by endocytosis and low pH-dependent fusion with endosomes. The precise sequence of receptor engagement and their roles in promoting HCV E1E2 glycoprotein-mediated fusion are poorly characterized. Because cell-free HCV tolerates an acidic environment, we hypothesized that binding to one or more receptors on the cell surface renders E1E2 competent to undergo low pH-induced conformational changes and promote fusion with endosomes. To test this hypothesis, we examined the effects of low pH and of the second extracellular loop (ECL2) of CD81, one of the four entry factors, on HCV infectivity. Pretreatment with an acidic buffer or with ECL2 enhanced infection through changing the E1E2 conformation, as evidenced by the altered reactivity of these proteins with conformation-specific antibodies and stable association with liposomes. However, neither of the two treatments alone permitted direct fusion with the cell plasma membrane. Sequential HCV preincubation with ECL2 and acidic buffer in the absence of target cells resulted in a marked loss of infectivity, implying that the receptor-bound HCV is primed for low pH-dependent conformational changes. Indeed, soluble receptor-pretreated HCV fused with the cell plasma membrane at low pH under conditions blocking an endocytic entry pathway. These findings suggest that CD81 primes HCV for low pH-dependent fusion early in the entry process. The simple triggering paradigm and intermediate conformations of E1E2 identified in this study could help guide future vaccine and therapeutic efforts to block HCV infection. |
| Databáze: | OpenAIRE |
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