title: Interacting regions of CD81 and two of its partners, EWI-2 and EWI-2wint, and their effect on hepatitis C virus infection.
abstract: CD81 is a tetraspanin protein that is involved in several essential cellular functions, as well as in the hepatitis C virus (HCV) infection. CD81 interacts with a high stoichiometry with its partner proteins EWI-2, EWI-2wint, and EWI-F. These latter proteins modify the functions of CD81 and can thereby potentially inhibit infection or modulate cell migration. Here, we characterized the cleavage of EWI-2 leading to the production of EWI-2wint, which has been shown to inhibit HCV infection. We determined the regions of EWI-2/EWI-2wint and CD81 that are important for their interaction and their functionality. More precisely, we identified a glycine zipper motif in the transmembrane domain of EWI-2/EWI-2wint that is essential for the interaction with CD81. In addition, we found that palmitoylation on two juxtamembranous cysteines in the cytosolic tail of EWI-2/EWI-2wint is required for their interaction with CD81 as well as with CD9, another tetraspanin. Thus, we have shown that palmitoylation of a tetraspanin partner protein can influence the interaction with a tetraspanin. We therefore propose that palmitoylation not only of tetraspanins, but also of their partner proteins is important in regulating the composition of complexes in tetraspanin networks. Finally, we identified the regions in CD81 that are necessary for its functionality in HCV entry and we demonstrated that EWI-2wint needs to interact with CD81 to exert its inhibitory effect on HCV infection.
authors.affiliation: Center for Infection and Immunity of Lille, Hepatitis C Laboratory, University Lille Nord de France, CNRS UMR8204, INSERM U1019, Pasteur Institute of Lille, 59021 Lille, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Montpellier
authors.forename: Birke Andrea
authors.initials: BA
authors.lastname: Tews
authors.forename: Julien
authors.initials: J
authors.lastname: Poitrimole
authors.forename: Vera
authors.initials: V
authors.lastname: Rocha-Perugini
authors.forename: Valentina
authors.initials: V
authors.lastname: D'Arienzo
authors.forename: Julie
authors.initials: J
authors.lastname: Potel
authors.forename: Xin A
authors.initials: XA
authors.lastname: Zhang
authors.forename: Eric
authors.initials: E
authors.lastname: Rubinstein
authors.forename: Jean
authors.initials: J
authors.lastname: Dubuisson
authors.forename: Laurence
authors.initials: L
authors.lastname: Cocquerel
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry*; D019921:Biotinylation; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003600:Cytosol / Q000378:metabolism; D005998:Glycine / Q000737:chemistry; D016174:Hepacivirus / Q000378:metabolism*; D006526:Hepatitis C / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry; D008565:Membrane Proteins / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D060225:Tetraspanin 28; D060245:Tetraspanin 29; D059470:Tetraspanins
chemical_list: D015703:Antigens, CD; C554798:CD81 protein, human; C554869:CD9 protein, human; C440028:IGSF8 protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C508125:TSPAN1 protein, human; D060225:Tetraspanin 28; D060245:Tetraspanin 29; D059470:Tetraspanins; D005998:Glycine