The small extracellular loop of CD81 is necessary for optimal surface expression of the large loop, a putative HCV receptor

Human tetraspanin CD81 is a putative receptor for hepatitis C virus (HCV), because it has been shown to bind ‘bona fide’ HCV particles. CD81, as all tetraspanins, spans the membrane four times forming two extracellular loops: a small (SEL) and a large one (LEL). We have shown previously that a recombinant form of LEL is sufficient for binding HCV through the major envelope glycoprotein E2. The role of SEL in the CD81–HCV interaction was questioned. We found that transfectants expressing LEL alone bind the recombinant HCV-E2 protein at much lower levels than cells expressing the wild type CD81. And therefore whether SEL contributes to the CD81–HCV interaction or whether it influences the expression of LEL was examined. We have found that in the absence of SEL, LEL is expressed at significantly reduced levels on the cell surface because it is retained intracellularly, while HCV-E2 still binds LEL. Our data suggest that SEL of CD81 does not mediate interaction with HCV, but contributes to optimal cell surface expression of LEL by mediating translocation of the whole CD81 molecule to the cell surface.