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The hepatitis B x antigen effector, URG7, blocks tumour necrosis factor -mediated apoptosis by activation of phosphoinositol 3-kinase and -catenin

Mark A. Feitelson^1,3,

¹ Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
² Jefferson Medical School, Thomas Jefferson University, Philadelphia, PA, USA
³ Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

Correspondence
Mark A. Feitelson
mfeitelson1{at}yahoo.com
or
feitelso{at}temple.edu

Hepatitis B x antigen (HBxAg) contributes significantly to the pathogenesis of chronic infection and development of hepatocellular carcinoma. To discern some of its operative pathways, HepG2 cells were stably transduced with HBx or the bacterial chloramphenicol acetyltransferase (CAT) gene. Differential gene expression has previously revealed an upregulated gene, clone 7 (URG7), that conferred resistance to anti-Fas killing on HepG2X cells. Given that tumour necrosis factor alpha (TNF) is also an important mediator of chronic hepatitis, and partially shares signalling with Fas, experiments were designed to test whether URG7 blocks TNF killing of HepG2X cells. HepG2X cells expressing URG7 and HepG2 cells overexpressing URG7 in the absence of HBxAg were resistant to TNF killing compared with HepG2CAT cells. URG7 small interfering RNA restored the sensitivity of HepG2X cells to TNF killing. Killing was associated with the activation of caspases 3 and 8, suggesting that URG7 blocked these caspases. This resistance was also associated with activation of phosphoinositol 3-kinase/Akt. Given that Akt and HBxAg also activate -catenin, experiments were designed to determine whether URG7 blocked apoptosis via activation of -catenin. Both HBxAg and URG7 activated fragments of the -catenin promoter, and also promoted expression of -catenin target genes. Hence, URG7 inhibits TNF-mediated killing by blocking one or more caspases in the apoptotic pathway and by activating phosphoinositol 3-kinase and -catenin, thereby overriding the apoptotic signalling of TNF. This suggests that URG7 helps to protect virus-infected hepatocytes during chronic hepatitis B virus infection.

Present address: Suite 409 BioLife Science Building, Department of Biology, College of Science and Technology, Temple University, 1900 North 12th Street, Philadelphia, PA 19122, USA.