HBX PROTEIN OF HEPATITIS-B VIRUS ACTIVATES JAK1-STAT SIGNALING

The X-gene product (HBx) of the hepatitis B virus plays essential role s in viral replication and the generation of hepatocellular carcinoma. Although the mechanism for HBx action is unclear, HBx may exert its p leiotropic functions through the stimulation of signal transduction pa thways including the Ras/mitogen-activated protein kinase cascade and/ or inactivation of the p53 function. Here, we investigated whether HBx has the ability to activate the Jak-STAT signaling pathway. As a firs t step, we established stable cell lines constitutively expressing HBx , In these HBx-expressing stable cells, the tyrosine phosphorylation o f various STATs, including STAT3 and -5, was constitutively enhanced b y HBx, and the concomitant increase in STAT-dependent DNA binding and transcriptional activation was observed. Furthermore, HBx specifically elevated tyrosine phosphorylation and in vitro kinase activity of Jak 1, but not Jak2 or Tyk2, through protein to protein interaction with J ak1. These results clearly establish HBx as the inducer of the Jak-STA T signaling pathway, and at the same time, HBx-mediated Jak-STAT activ ation may provide a novel mechanism for the pleiotropic functions of H Bx, including transformation and promiscuous transcriptional activatio n.