Hepatitis B virus core protein inhibits Fas‐mediated apoptosis of hepatoma cellsviaregulation of mFas/FasL and sFas expression

Abstract

Hepatitis B virus core protein (HBc) has been implicated in hepatocarcinogenesis through several mechanisms. Resistance of hepatitis B virus (HBV)-infected hepatocytes to apoptosis is considered one of the major contributors to the progression of chronic hepatitis to cirrhosis and ultimately to hepatocellular carcinoma. The Fas receptor/ligand (Fas/FasL) system plays a prominent role in hepatocyte death during HBV infection. Here we report that HBc mediates resistance of hepatoma cells to agonistic anti-Fas antibody (CH11)-induced apoptosis. When HBc was introduced into human hepatoma cells, the cells became resistant to CH11 cytotoxicity in a p53-dependent manner. HBc significantly down-regulated the expression of p53, total Fas, and membrane-bound Fas at the mRNA and protein levels and reduced FasL mRNA expression. In contrast, HBc up-regulated the expression of soluble forms of Fas by increasing Fas alternative mRNA splicing. Mechanistically, HBc-mediated Fas alternative mRNA splicing was associated with up-regulation of polypyrimidine tract-binding protein 1 and down-regulation of Fas-activated serine/threonine kinase. These results indicated that HBc may prevent hepatocytes from Fas-induced apoptosis by the dual effects of reducing the expression of the proapoptotic form of Fas and enhancing the expression of the antiapoptotic form of the receptor, which may contribute to the survival and persistence of infected hepatocytes during chronic infection.

Fas-FasL expression and myocardial cell apoptosis in patients with viral myocarditis

“…Between 7 and 14 days after the initial onset of the viral infection, most of the infiltrated cells are T-cells, which become CTLs when activated, and are programmed to kill target cells (Chen et al, 2014;Grygorczuk et al, 2015;Shi et al, 2015;Tao et al, 2015). There are two primary means by which CTLs kill target cells: one is perforin/granzyme-mediated and the other involves the Fas-FasL signaling pathway (Arai et al, 2014;Gmeiner et al, 2015;Liu et al, 2015;Nallapalle et al, 2015;O'Donnell et al, 2015;Saigusa et al, 2015). Through the presentation of Fas by CTLs to FasL on target cells, Fas-FasL signaling passes programmed cell death signals to myocardial cells, which leads to apoptosis in a relatively short time frame (Fernandes et al, 2014;Nabhani et al, 2014;O'Reilly et al, 2015;Zhang et al, 2015).…”

Chronic hepatitis B and non‐alcoholic fatty liver disease: Conspirators or competitors?

“…Increased autophagy and inhibited apoptosis in HBV‐infected cells are known to inhibit the antiviral responses towards HBV‐infected cells, consequently guaranteeing the virus replication in these cells . Conversely, inhibition of autophagy can incur the death of HBV‐infected cells .…”

Alternative RNA Splicing in the Pathogenesis of Liver Disease

“…Consequently, omega-3 and omega-6 poly-unsaturated fatty acids were reduced following Ptbp1 knockdown, but saturated and mono-unsaturated fatty acids were not altered. Interestingly, PTBP1 is upregulated during hepatitis B virus infection and reduces expression of the proapoptotic form of FAS, which may contribute to the survival of infected hepatocytes (64). …”