HEPATITIS-C VIRUS CORE PROTEIN INTERACTS WITH THE CYTOPLASMIC TAIL OFLYMPHOTOXIN-BETA RECEPTOR

Hepatitis C virus (HCV) core protein is a multifunctional protein. We examined whether it can interact with cellular proteins, thus contribu ting to viral pathogenesis. Using the HCV core protein as a bait to sc reen a human liver cDNA library in a yeast two-hybrid screening system , we have isolated several positive clones encoding cellular proteins that interact with the HCV core protein. Interestingly, more than half of these clones encode the cytoplasmic domain of lymphotoxin-beta rec eptor (LT beta R), which is a member of the tumor necrosis factor rece ptor family. Their binding was confirmed by in vitro glutathione S-tra nsferase fusion protein binding assay and protein-protein blotting ass ay to be direct and specific. The binding sites were mapped within a 5 8-amino-acid region of the cytoplasmic tail of LT beta R. The binding site in the HCV core protein was localized within amino acid residues 36 to 91 from the N terminus, corresponding to the hydrophilic region of the protein. In mammalian cells, the core protein was found to be a ssociated with the membrane-bound LT beta R. Since the LT beta R is in volved in germinal center formation and developmental regulation of pe ripheral lymphoid organs, lymph node development, and apoptotic signal ing, the binding of HCV core protein to LT beta R suggests the possibi lity that this viral protein has an immunomodulating function and may explain the mechanism of viral persistence and pathogenesis of HCV.