ACTIVATION OF HEPATITIS-B VIRUS S-PROMOTER BY THE VIRAL LARGE SURFACEPROTEIN VIA INDUCTION OF STRESS IN THE ENDOPLASMIC-RETICULUM

Hepatitis B virus (HBV) codes for three forms of surface protein, The minor, large form is translated from transcripts specified by the preS 1 promoter, while the middle and small forms are translated from trans cripts specified by the downstream S promoter, When the large surface protein is overexpressed, the secretion of both subviral and virion pa rticles is blocked within the secretory pathway, We show here that ove rexpression of the large surface protein leads to up to a 10-fold acti vation of the S promoter but not of an unrelated promoter, Neither the middle nor the small surface protein, nor a secretable form of the la rge surface protein, activates the S promoter, but agents that induce endoplasmic reticulum (ER) stress have an effect similar to that of th e large surface protein, The large surface protein also activates the S promoter in the contest of the entire viral genome, Therefore, it ap pears that HBV has evolved a feedback mechanism, such that ER stress i nduced by accumulation of the large surface protein increases the synt hesis of the middle and small surface proteins, which in combination w ith the large surface protein can form mixed, secretable particles, In addition, like other agents that induce ER stress, the large surface protein can activate the cellular grp78 and grp94 promoters, raising t he possibility that it may alter the physiology of the host cell.