Hepatitis B spliced protein (HBSP) suppresses Fas-mediated hepatocyte apoptosis via activation of PI3K/Akt signaling.

Hepatitis B spliced protein (HBSP) is known to associate with viral persistence and pathogenesis, however, its biological and clinical significance remains poorly defined. Acquired resistance to Fas-mediated apoptosis is thought as one of the major promotors for hepatitis B virus (HBV) chronicity and malignancy. The purpose of this study was to investigate whether HBSP could protect hepatocytes against Fas-initiated apoptosis. We showed here that HBSP mediated resistance of hepatoma cells or primary human hepatocytes (PHH) to agonistic anti-Fas antibody (CH11)- or FasL-induced apoptosis. Under Fas signaling stimulation, expression of HBSP inhibited Fas aggregation and prevented recruitment of the adaptor molecule Fas-associated death domain (FADD) and procaspase-8 (or FADD like interleukin 1 β-converting enzyme, FLICE) into the death-inducing signaling complex (DISC), while increasing recruitment of cellular FLICE-inhibitory protein L (FLIPL ) into the DISC. Those effects may be mediated through activation of PI3K/AKT pathway as evidenced by increased cellular PIP3 content and PI3K activity, and enhanced phosphorylation of mTORC2 and PDPK1 as well as Akt itself. Confirmedly, inhibition of PI3K by LY294002 reversed the effect of HBSP on Fas aggregation, FLIPL expression and cellular apoptosis. These results indicate that HBSP functions to prevent hepatocytes from Fas-induced apoptosis by enhancing PI3K/Akt activity, which may contribute to the survival and persistence of infected hepatocytes during chronic infection. Importance: Our study revealed a previously unappreciated role of HBSP in Fas-mediated apoptosis. The anti-apoptotic activity of HBSP is important for understanding hepatitis B pathogenesis. In particular, HBV variants associated with hepatoma carcinoma may down-regulate apoptosis of hepatocytes through enhanced HBSP expression. Our study also found that AKT is centrally involved in Fas-induced hepatocyte apoptosis and revealed interventions directed at inhibiting the activation or functional activity of AKT may be of therapeutic value in this process.