Envelope protein-mediated down-regulation of hepatitis B virus receptor in infected hepatocytes.
Entry of duck hepatitis B virus (DHBV) is initiated by specific interaction of its large envelope protein (L) with a cellular entry receptor, recently identified as carboxypeptidase D (CPD; historically gp180). In this report, we present evidence demonstrating that this receptor is down-regulated as a result of DHBV infection: (i) receptor levels determined by Western blot were much reduced in DHBV-infected duck livers and undetectable by immunostaining in infected cultured hepatocytes; (ii) results from metabolic labeling experiments indicate enhanced receptor protein turnover; (iii) the kinetics of receptor loss from newly infected cells correlated with the accumulation of newly synthesized viral protein; (iv) expression of DHBV L protein, transduced from a recombinant adenovirus, was sufficient to eliminate gp180/CPD from the Golgi compartment, its normal predominant location; (v) gp180/CPD remained absent from the Golgi compartment in infected hepatocytes, even after overexpression from a recombinant adenovirus, while residual amounts subsequently became detectable in a perinuclear compartment, containing DHBV L protein; (vi) expression of DHBV L protein in a HepG2 cell line, stably expressing gp180/CPD, leads to incomplete receptor maturation and induces its degradation. Taken together, these data are consistent with a model in which the virus receptor interacts early in the biosynthetic pathway with the viral L protein, leading to its retention in a pre-Golgi compartment and to subsequent degradation, thus preventing receptor interference with the export of DHBV via the secretory pathway which it shares with its receptor. Accordingly, and analogously with receptor down-regulation in retroviral systems, DHBV receptor down-modulation may account for the much-reduced efficiency of DHBV superinfection of preinfected hepatocytes.
Breiner
K M
KM
Mikrobiologie and Zentrum für Molekulare Biologie, Universität Heidelberg, 69120 Heidelberg, Germany.
Urban
S
S
Glass
B
B
Schaller
H
H
D000818:Animals; D002268:Carboxypeptidases / Q000032:analysis* / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D004372:Ducks; D006056:Golgi Apparatus / Q000821:virology; D022781:Hepatocytes / Q000821:virology*; D006801:Humans; D008099:Liver / Q000821:virology; D011817:Rabbits; D011991:Receptors, Virus / Q000032:analysis*; D014162:Transfection; D014759:Viral Envelope Proteins / Q000032:analysis / Q000502:physiology*
D011991:Receptors, Virus; D014759:Viral Envelope Proteins; D002268:Carboxypeptidases; C078874:carboxypeptidase D