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Hepatitis C Virus Envelope Glycoprotein E1 Forms Trimers at the Surface of the Virion

dc.contributor.authorFALSON, Pierre
dc.contributor.authorBARTOSCH, Birke
dc.contributor.authorALSALEH, Khaled
dc.contributor.authorTEWS, Birke Andrea
dc.contributor.authorLOQUET, Antoine
dc.contributor.authorCICZORA, Yann
dc.contributor.authorRIVA, Laura
dc.contributor.authorMONTIGNY, Cedric
dc.contributor.authorMONTPELLIER, Claire
dc.contributor.authorDUVERLIE, Gilles
dc.contributor.authorPECHEUR, Eve-Isabelle
dc.contributor.authorLE MAIRE, Marc
dc.contributor.authorCOSSET, Francois-Loic
dc.contributor.authorDUBUISSON, Jean
dc.contributor.authorPENIN, Francois
dc.date.accessioned2020-09-03T08:02:11Z
dc.date.available2020-09-03T08:02:11Z
dc.date.issued2015
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/10984
dc.description.abstractEnUNLABELLED: In hepatitis C virus (HCV)-infected cells, the envelope glycoproteins E1 and E2 assemble as a heterodimer. To investigate potential changes in the oligomerization of virion-associated envelope proteins, we performed SDS-PAGE under reducing conditions but without thermal denaturation. This revealed the presence of SDS-resistant trimers of E1 in the context of cell-cultured HCV (HCVcc) as well as in the context of HCV pseudoparticles (HCVpp). The formation of E1 trimers was found to depend on the coexpression of E2. To further understand the origin of E1 trimer formation, we coexpressed in bacteria the transmembrane (TM) domains of E1 (TME1) and E2 (TME2) fused to reporter proteins and analyzed the fusion proteins by SDS-PAGE and Western blotting. As expected for strongly interacting TM domains, TME1-TME2 heterodimers resistant to SDS were observed. These analyses also revealed homodimers and homotrimers of TME1, indicating that such complexes are stable species. The N-terminal segment of TME1 exhibits a highly conserved GxxxG sequence, a motif that is well documented to be involved in intramembrane protein-protein interactions. Single or double mutations of the glycine residues (Gly354 and Gly358) in this motif markedly decreased or abrogated the formation of TME1 homotrimers in bacteria, as well as homotrimers of E1 in both HCVpp and HCVcc systems. A concomitant loss of infectivity was observed, indicating that the trimeric form of E1 is essential for virus infectivity. Taken together, these results indicate that E1E2 heterodimers form trimers on HCV particles, and they support the hypothesis that E1 could be a fusion protein. IMPORTANCE: HCV glycoproteins E1 and E2 play an essential role in virus entry into liver cells as well as in virion morphogenesis. In infected cells, these two proteins form a complex in which E2 interacts with cellular receptors, whereas the function of E1 remains poorly understood. However, recent structural data suggest that E1 could be the protein responsible for the process of fusion between viral and cellular membranes. Here we investigated the oligomeric state of HCV envelope glycoproteins. We demonstrate that E1 forms functional trimers after virion assembly and that in addition to the requirement for E2, a determinant for this oligomerization is present in a conserved GxxxG motif located within the E1 transmembrane domain. Taken together, these results indicate that a rearrangement of E1E2 heterodimer complexes likely occurs during the assembly of HCV particles to yield a trimeric form of the E1E2 heterodimer. Gaining structural information on this trimer will be helpful for the design of an anti-HCV vaccine.
dc.language.isoen
dc.title.enHepatitis C Virus Envelope Glycoprotein E1 Forms Trimers at the Surface of the Virion
dc.typeArticle de revue
dc.identifier.doi10.1128/jvi.00991-15
dc.subject.halChimie/Matériaux
bordeaux.journalJournal of virology
bordeaux.page10333-46
bordeaux.volume89
bordeaux.hal.laboratoriesInstitut de Chimie & de Biologie des Membranes & des Nano-objets (CBMN) - UMR 5248*
bordeaux.hal.laboratoriesInstitut de Chimie & de Biologie des Membranes & des Nano-objets (CBMN, UMR 5248)
bordeaux.issue20
bordeaux.institutionUniversité de Bordeaux
bordeaux.institutionBordeaux INP
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