Enhancement of Tumor Necrosis Factor-α–Mediated Hepatic Apoptosis and Liver Injury by Hepatitis B Virus Surface Antigen

Tumor necrosis factor-α (TNF-α) is a highly pleiotropic cytokine with a variety of biological functions, such as cell proliferation, metabolic activation, inflammatory response, and cell death. TNF-α can induce a variety of mechanisms to initiate hepatocyte apoptosis, resulting in subsequent liver damage. Hepatitis B virus surface antigen (HBsAg) is the most abundant hepatitis B virus protein in the hepatocyte during chronic virus infection. However, its role in TNF-α–mediated apoptosis of hepatocytes has not been revealed. We report here that HBsAg promotes TNF-α–mediated hepatocyte apoptosis through inhibiting TNF-α–mediated anti-apoptotic complex I–dependent NF-κB activation and enhancing TNF-α–mediated pro-apoptotic complex II assembly. Mechanistically, HBsAg-mediated inhibition of complex I assembly was associated with down-regulation of K63-linked receptor-interacting protein kinase 1 (RIPK1) ubiquitination through repression of cellular inhibitor of apoptosis protein-1 (cIAP1) expression. Secretion-deficient HBsAg variant S204R enhances their pro-apoptotic abilities via further inhibition of RIPK1 ubiquitination. Expression of HBsAg in mice injected with recombinant adenovirus-associated virus 8 promoted D-galactosamine/lipopolysaccharide–induced TNF-α–mediated liver injury and damage by a mouse model. In conclusion, HBsAg may predispose hepatocytes to TNF-α–mediated apoptosis and mice to acute liver injury by switching TNF-α–mediated anti-apoptotic complex I to pro-apoptotic complex II, showing novel insights into the underlying mechanisms of hepatitis B virus–associated liver injury.