HTLV Type 1 Envelope Glycoprotein gp46 Evokes Necrosis by Binding to Receptor Complex

Abstract

In syncytium formation induced by HTLV-1-bearing cells, 71-kDa heat shock cognate protein (HSC70) functions as a receptor molecule and the receptor complex with β-actin and palmitoyl(16:0)-oleoyl(18:1)-phosphatidylglycerol(PG) is thus formed. We now have evidence that the molecular association between HTLV-1 gp46 envelope protein and HSC70 led to pore formation on the surface of target cell membrane and cell death followed. The peptide segment corresponding to the region from Asp-197 to Leu-216 (gp46-197), and which serves as a binding site to both HSC70 and PG for syncytium formation, also had cytotoxic effects on target cell MOLT-4. This cytotoxicity was due to necrosis, not apoptosis. On the other hand, two other receptor-binding sites, Lys-111 to Asp-138 on gp46 (gp46-111) and Cys-400 to Leu-429 on gp21 (gp21-400), and which bound only with PG, had no cytotoxic effects on MOLT-4 cells. The HTLV-2 peptide (gp46-194; Glu194 to Leu-213) corresponding to the region of HTLV-1 gp46-197 showed no cytotoxicity, and interacted only with PG, not with either HSC70 or β-actin. Amino acid alterations between HTLV-1 gp46-197 and HTLV-2 gp46-194 were significant on the hydrophilic face of the amphipathic structure. Taken together, the interaction between HSC70 and gp46 of HTLV-1 through the hydrophilic face of gp46-197 may lead to pore formation in lipid bilayers to be followed by membrane fusion or cell death.