Glucose-regulated protein 78 demonstrates antiviral effects but is more suitable for hepatocellular carcinoma prevention in hepatitis B

Abstract

BackgroundHepatitis B virus (HBV) is the leading cause of liver cirrhosis and hepatocellular carcinoma in Asia and Africa. Existing antivirals cannot cure HBV or eliminate risk of hepatocellular carcinoma. Glucose-regulated protein 78 (GRP78) can inhibit HBV replication, but promote virion secretion and hepatocellular cancer cell invasion. For these reasons, the overall effect of GRP78 on HBV production and whether to utilize the HBV replication-inhibitory effect of GRP78 up-regulation or the hepatocellular cancer cell invasion-inhibitory effect of its down-regulation were further investigated in order to improve the efficacy of current antiviral therapy.MethodsGRP78 regulations in HepG2.2.15 cells were conducted by transfections of expressing vector and small interfering RNA, respectively. The changes in HBV replication, hepatitis B e antigen (HBeAg) synthesis and hepatoma cell motility were monitored.ResultsGRP78 overall decreased HBV production due to its HBV replication-inhibitory effect time-dependently overwhelming virion secretion-promoting effect in HepG2.2.15 cells. Unlike the parental cells (HepG2), HepG2.2.15 cells demonstrated decreased expressions of the major genes in the interferon-β1-dependent pathway. Moreover, the expressions of these genes were not affected by GRP78 regulations. However, GRP78 was found to inhibit HBeAg secretion and to increase the retro-transportation of capsid assembly-interfering HBeAg precursor from the endoplasmic reticulum into the cytosol where new viral nucleocapsids formed. Furthermore, GRP78 overexpression promoted wound healing process (the motility) of HepG2.2.15 cells. In contrast, GRP78 knockdown enhanced HBV replication and HBeAg secretion, but they were abolished by entecavir and furin inhibitor, respectively.ConclusionsGRP78 mainly demonstrates anti-HBV effects, reducing HBV production and HBeAg secretion. With due regard to the hepatocellular cancer invasion risk of the overexpression and the rectifiability of the unpleasant effects of the knockdown, GRP78 down-regulation may be more suitable to serve as an additive strategy to cover the hepatocellular cancer prevention shortage of current antiviral therapy in the future.

Regulation of Molecular Chaperone GRP78 by Hepatitis B Virus: Control of Viral Replication and Cell Survival

“…However, in contrast to the data from Ma et al, our results showed that GRP78 overexpression did not activate the IFN signaling in both HBV-replicating Huh7 and HepAD38 cells, although RIG-IN, as a positive control, activated type I IFN signaling dramatically. In agreement with our data, Zheng et al (20) also reported that IFN signaling might not be responsible for GRP78 inhibition of HBV. In addition, since transformed cell lines like HepG2 have defects in IFN signaling (43,44), it is also intriguing that GRP78 can inhibit HBV replication by activating type I signaling in these cell lines.…”

Release of hepatitis B virions is positively regulated by glucose‐regulated protein 78 through direct interaction with preS1

“… 26 Furthermore, GRP78 can be galactosylated at three residues, participates in viral entry into the host cell, and/or regulates the replication of viruses, including MERS‐CoV, JEV, EBOV, HCV, and HBV. 18 , 19 , 27 , 28 , 29 …”

HBV enveloped particle secretion is positively regulated by GRP78 through direct interaction with preS1

“…GRP78 could be galactosylated at three residues and might result in increased molecular weight, which further confirmed previous findings (28,29). Additionally, GRP78 is localized in the lumen of the ER, is involved in viral entry into the host cell, and/or regulates the replication of viruses, such as MERS-CoV, JEV, EBOV, HCV, and HBV (19,20,30). Confocal immunofluorescence detection revealed that both GRP78 and preS1 were spatially colocalized and mainly distributed in the cytoplasm (Fig.…”