PHOSPHORYLATION AND NUCLEAR-LOCALIZATION OF THE HEPATITIS-B VIRUS CORE PROTEIN - SIGNIFICANCE OF SERINE IN THE 3 REPEATED SPRRR MOTIFS

Hepatitis B virus core protein (antigen) is an important serologic mar ker of hepatitis B virus infection. This protein is found in the cytop lasm or the nuclei, or both, of infected hepatocytes. A nuclear locali zation signal has previously been identified in the core protein seque nce. This signal overlaps three repeated SPRRR motifs. In this report, we demonstrate that substitution of all of the serine residues in the se three SPRRR motifs with alanine tan prevent almost entirely the pho sphorylation of the core protein in Huh-7 hepatoma cells, enhance nucl ear localization of the core protein in both Huh-7 and nonhepatic cell s, and abolish cell cycle regulation of nuclear localization of the co re protein. Since the three core protein mutants which retained only o ne serine residue of each of the three SPRRR motifs could be phosphory lated to similar degrees, these three serine residues likely could ser ve as the acceptor sites for phosphorylation with equal efficiency. Th ese results, together,vith the observation that the three SPRRR motifs overlap the nuclear localization signal of the core protein, raise th e possibility that nuclear localization of the core protein is negativ ely regulated by phosphorylation of the serine residues in the SPRRR m otifs.