Hepatitis C virus NS2 protein triggers endoplasmic reticulum stress and suppresses its own viral replication

Bussche, Annette von dem; Machida, Raiki; Li, Ké; Loevinsohn, Gideon; Khander, Amrin; Wang, Jianguo; Wakita, Takaji; Wands, Jack R.; Li, Jisu

doi:10.1016/j.jhep.2010.05.022

Cited by 45 publications

(42 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…To validate and further characterize the secreted GRP78 in JEV-induced secretion medium, both intracellular extracts and secretion medium samples from mock-infected and JEV-infected cells were analyzed by Western blot. The detection of GRP78 from mock-infected and JEV-infected intracellular extracts were similar (Figure 3A), indicating that the GRP78 expression was not induced due to JE virus infection, which is in contrast with other reports [11,12,14,21]. Note that, the two upper bands shown in the JEV-infected secretion medium were probably GRP94 according to the report published by the Liberman group [22].…”

Section: Resultsmentioning

confidence: 53%

Japanese encephalitis virus co-opts the ER-stress response protein GRP78 for viral infectivity

Chang

Hung

et al. 2011

Virol J

View full text Add to dashboard Cite

The serum-free medium from Japanese encephalitis virus (JEV) infected Baby Hamster Kidney-21 (BHK-21) cell cultures was analyzed by liquid chromatography tandem mass spectrometry (LC-MS) to identify host proteins that were secreted upon viral infection. Five proteins were identified, including the molecular chaperones Hsp90, GRP78, and Hsp70. The functional role of GRP78 in the JEV life cycle was then investigated. Co-migration of GRP78 with JEV particles in sucrose density gradients was observed and co-localization of viral E protein with GRP78 was detected by immunofluorescence analysis in vivo. Knockdown of GRP78 expression by siRNA did not effect viral RNA replication, but did impair mature viral production. Mature viruses that do not co-fractionate with GPR78 displayed a significant decrease in viral infectivity. Our results support the hypothesis that JEV co-opts host cell GPR78 for use in viral maturation and in subsequent cellular infections.

show abstract

Section: Resultsmentioning

confidence: 53%

Japanese encephalitis virus co-opts the ER-stress response protein GRP78 for viral infectivity

Chang

Hung

et al. 2011

Virol J

View full text Add to dashboard Cite

show abstract

“…In the course of virus productive infection, a large amount of viral proteins is synthesized in infected cells, where unfolded or misfolded proteins result in ER stress (23). The accumulation of viral envelope proteins in the ER has been implicated as the trigger of the UPR in several virus infections (6,7,12,52,84). For HBV, there are three envelopment proteins.…”

Section: Discussionmentioning

confidence: 99%

Subversion of Cellular Autophagy Machinery by Hepatitis B Virus for Viral Envelopment

Liu

Wang

et al. 2011

J Virol

239

296

View full text Add to dashboard Cite

Autophagy is a conserved eukaryotic mechanism that mediates the removal of long-lived cytoplasmic macromolecules and damaged organelles via a lysosomal degradative pathway. Recently, a multitude of studies have reported that viral infections may have complex interconnections with the autophagic process. The findings reported here demonstrate that hepatitis B virus (HBV) can enhance the autophagic process in hepatoma cells without promoting protein degradation by the lysosome. Mutation analysis showed that HBV small surface protein (SHBs) was required for HBV to induce autophagy. The overexpression of SHBs was sufficient to induce autophagy. Furthermore, SHBs could trigger unfolded protein responses (UPR), and the blockage of UPR signaling pathways abrogated the SHB-induced lipidation of LC3-I. Meanwhile, the role of the autophagosome in HBV replication was examined. The inhibition of autophagosome formation by the autophagy inhibitor 3-methyladenine (3-MA) or small interfering RNA duplexes targeting the genes critical for autophagosome formation (Beclin1 and ATG5 genes) markedly inhibited HBV production, and the induction of autophagy by rapamycin or starvation greatly contributed to HBV production. Furthermore, evidence was provided to suggest that the autophagy machinery was required for HBV envelopment but not for the efficiency of HBV release. Finally, SHBs partially colocalized and interacted with autophagy protein LC3. Taken together, these results suggest that the host's autophagy machinery is activated during HBV infection to enhance HBV replication.Hepatitis B virus (HBV) is a noncytopathic, enveloped DNA virus that belongs to the family Hepadnaviridae (57, 70). It is one of the most successful human pathogens, with an estimated 2 billion people infected worldwide, of whom 400 million have chronic HBV infection (54). Chronic HBV infection is correlated with a strongly increased risk for the development of liver cirrhosis and hepatocellular carcinoma (HCC) (49, 54).Effective preventive vaccines against HBV have been available for nearly three decades; however, their effectiveness in preventing blood-borne transmission from an infected mother to her newborn is about 90% (77), and therapeutic vaccines for the treatment of established hepatitis B infection are not available (65, 67). Currently, two types of antiviral therapies are approved: pegylated alpha interferon and nucleoside/nucleotide analogues (60). However, these antivirals cannot completely eradicate the virus, and their efficacy in preventing liver cirrhosis and HCC is limited (21, 64). Thus, the details of the host-virus relationship during HBV infection urgently need to be further clarified to facilitate the development of efficient therapeutic strategies for the control of HBV infection.Autophagy, an evolutionarily conserved intracellular process, involves the formation of a double membrane structure, called the autophagosome, which engulfs long-lived cytoplasmic macromolecules and damaged organelles and delivers them to lysosomes for degrada...

show abstract

“…To calculate OGG1 activity, the 3′ product and the uncut substrate band in the autoradiograms as well as OGG1 expression and beta actin levels measured by western blot were quantified by densitometry using ImageQuantTL software (GE Healthcare Life Sciences). The activity was corrected for transfection efficiency and protein loading among the different samples using the formula outlined below (34). …”

Section: Methodsmentioning

confidence: 99%

Inactivation of a common OGG1 variant by TNF-alpha in mammalian cells

et al. 2015

View full text Add to dashboard Cite

Reactive oxygen species threaten genomic integrity by inducing oxidative DNA damage. One common form of oxidative DNA damage is the mutagenic lesion 8-oxoguanine (8-oxodG). One driver of oxidative stress that can induce 8-oxodG is inflammation, which can be initiated by the cytokine tumor necrosis factor alpha (TNF-α). Oxidative DNA damage is primarily repaired by the base excision repair pathway, initiated by glycosylases targeting specific DNA lesions. 8-oxodG is excised by 8-oxoguanine glycosylase 1 (OGG1). A common Ogg1 allelic variant is S326C-Ogg1, prevalent in Asian and Caucasian populations. S326C-Ogg1 is associated with various forms of cancer, and S326C-OGG1 is inactivated by oxidation. However, whether oxidative stress caused by inflammatory cytokines compromises OGG1 variant repair activity remains unknown. We addressed whether TNF-α causes oxidative stress that both induces DNA damage and inactivates S326C-OGG1 via cysteine 326 oxidation. In mouse embryonic fibroblasts, we found that S326C-OGG1 was inactivated only after exposure to H2O2 or TNF-α. Treatment with the antioxidant N-acetylcysteine prior to oxidative stress rescued S326C-OGG1 activity, demonstrated by in vitro and cellular repair assays. In contrast, S326C-OGG1 activity was unaffected by potassium bromate, which induces oxidative DNA damage without causing oxidative stress, and presumably cysteine oxidation. This study reveals that Cys326 is vulnerable to oxidation that inactivates S326C-OGG1. Physiologically relevant levels of TNF-α simultaneously induce 8-oxodG and inactivate S326C-OGG1. These results suggest a mechanism that could contribute to increased risk of cancer among S326C-Ogg1 homozygous individuals.

show abstract

Hepatitis C virus NS2 protein triggers endoplasmic reticulum stress and suppresses its own viral replication

Cited by 45 publications

References 20 publications

Japanese encephalitis virus co-opts the ER-stress response protein GRP78 for viral infectivity

Japanese encephalitis virus co-opts the ER-stress response protein GRP78 for viral infectivity

Subversion of Cellular Autophagy Machinery by Hepatitis B Virus for Viral Envelopment

Inactivation of a common OGG1 variant by TNF-alpha in mammalian cells

Contact Info

Product

Resources

About