Zy. Hu et al., Hepatitis B virus X protein is both a substrate and a potential inhibitor of the proteasome complex, J VIROLOGY, 73(9), 1999, pp. 7231-7240
The hepatitis B virus X protein (HBX) is essential for the establishment of
HBV infection in vivo and exerts a pleiotropic effect on diverse cellular
functions. The yeast two-hybrid system had indicated that HBX could interac
t with two subunits of the 26S proteasome. Here we demonstrate an associati
on in vivo of HBX with the 26S proteasome complex by coimmunoprecipitation
and colocalization upon sucrose gradient centrifugation. Expression of HBX
in HepG2 cells caused a modest decrease in the proteasome's chymotrypsin- a
nd trypsin-like activities and in hydrolysis of ubiquitinated lysozyme, sug
gesting that HBX functions as an inhibitor of proteasome. In these cells, H
BX is degraded with a half-life of 30 min. Proteasome inhibitors retarded t
his rapid degradation and caused a marked increase in the level of HBX and
an accumulation of HBX in polyubiquitinated form. Thus, the low intracellul
ar level of HBX in due to rapid proteolysis by the ubiquitin-proteasome pat
hway. Surprisingly, the proteasome inhibitors blocked the transactivation b
y HBX, and this effect was not a result of a squelching phenomenon due to H
BX accumulation. Therefore, proteasome function is possibly required for th
e transactivation function of HBX. The inhibition of protein breakdown by p
roteasomes may account for the multiple actions of HBX and may be an import
ant feature of HBV infection, possibly in helping stabilize viral gene prod
ucts and suppressing antigen presentation.