Intracellular accumulation of subviral HBsAg particles and diminished Nrf2 activation in HBV genotype G expressing cells lead to an increased ROI level

Peiffer, Kai‐Henrik; Akhras, Sami; Himmelsbach, Kiyoshi; Hassemer, Matthias; Finkernagel, Malin; Carra, Gert; Nuebling, Michael; Chudy, M.; Niekamp, Hauke; Glebe, Dieter; Sarrazin, Christoph; Zeuzem, Stefan; Hildt, Eberhard

doi:10.1016/j.jhep.2014.11.028

Cited by 37 publications

(53 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is encoded by ORF, which supports the formation of three variants of surface antigen: small (S-domain), middle (preS2-S domains), and large (preS1-preS2-S domains) [282]. HBsAg is excreted from the cell even in the absence of other components of the virus [283]. However, some naturally-occurring mutants of the small HBsAg exhibit a reduced ability to be secreted and instead accumulate in the ER [264].…”

Section: Hepatitis C Virusmentioning

confidence: 99%

“…In turn, HBsAg-induced UPR induces a release of calcium ions into the cytoplasm, with subsequent enhancement of ROS production. An additional source of oxidative stress is a reduction of expression of the antioxidant defense Nrf2/ARE pathway [283] and protective enzymes, such as catalase and HO-1, in particular [264]. However, a study on the cohort of chronic hepatitis B patients failed to find any association between the mutations in pre-S domains of HBsAgs and the level of oxidative stress (as manifested by the DNA damage) [284].…”

Section: Hepatitis C Virusmentioning

confidence: 99%

“…Hepatitis B virus strongly induces the Nrf2/ARE pathway of antioxidant defense [283, 287]. It has been observed both in infected cell cultures and in liver tissues of chronic hepatitis B carriers [283, 287].…”

Section: Hepatitis C Virusmentioning

confidence: 99%

See 2 more Smart Citations

Oxidative stress, a trigger of hepatitis C and B virus-induced liver carcinogenesis

et al. 2016

View full text Add to dashboard Cite

Virally induced liver cancer usually evolves over long periods of time in the context of a strongly oxidative microenvironment, characterized by chronic liver inflammation and regeneration processes. They ultimately lead to oncogenic mutations in many cellular signaling cascades that drive cell growth and proliferation. Oxidative stress, induced by hepatitis viruses, therefore is one of the factors that drives the neoplastic transformation process in the liver. This review summarizes current knowledge on oxidative stress and oxidative stress responses induced by human hepatitis B and C viruses. It focuses on the molecular mechanisms by which these viruses activate cellular enzymes/systems that generate or scavenge reactive oxygen species (ROS) and control cellular redox homeostasis. The impact of an altered cellular redox homeostasis on the initiation and establishment of chronic viral infection, as well as on the course and outcome of liver fibrosis and hepatocarcinogenesis will be discussed The review neither discusses reactive nitrogen species, although their metabolism is interferes with that of ROS, nor antioxidants as potential therapeutic remedies against viral infections, both subjects meriting an independent review.

show abstract

Section: Hepatitis C Virusmentioning

confidence: 99%

Section: Hepatitis C Virusmentioning

confidence: 99%

See 1 more Smart Citation

Oxidative stress, a trigger of hepatitis C and B virus-induced liver carcinogenesis

et al. 2016

View full text Add to dashboard Cite

show abstract

“…In contrast to SHBs, the selective overexpression of LHBs leads to the formation of aggregates and is associated with the intracellular retention of HBsAg (43)(44)(45) that can lead to an intracellular accumulation (ground glass hepatocytes). Coexpression of SHBs can favor the secretion of LHBs (6). The formation and secretion efficiency of filaments depends on the relative amounts of SHBs and LHBs.…”

Section: Fig 4 Lhbs Enters Mvbs Even In the Absence Of Virion Productmentioning

confidence: 99%

“…The relevance of subviral particles for the viral life cycle is not fully understood. It has been reported that the release of viral particles is not directly affected by interference with the secretion of subviral particles (5,6), but they seem to enhance the infectivity of HBV (7). Apart from this, subviral particles are assumed to sequester HBV-specific antibodies.…”

mentioning

confidence: 99%

Subviral Hepatitis B Virus Filaments, like Infectious Viral Particles, Are Released via Multivesicular Bodies

Jiang

Himmelsbach

Ren

et al. 2016

J Virol

Self Cite

123

View full text Add to dashboard Cite

In addition to infectious viral particles, hepatitis B virus-replicating cells secrete large amounts of subviral particles assembled by the surface proteins, but lacking any capsid and genome. Subviral particles form spheres (22-nm particles) and filaments. Filaments contain a much larger amount of the large surface protein (LHBs) compared to spheres. Spheres are released via the constitutive secretory pathway, while viral particles are ESCRT-dependently released via multivesicular bodies (MVBs). The interaction of virions with the ESCRT machinery is mediated by ␣-taxilin that connects the viral surface protein LHBs with the ESCRT component tsg101. Since filaments in contrast to spheres contain a significant amount of LHBs, it is unclear whether filaments are released like spheres or like virions. To study the release of subviral particles in the absence of virion formation, a core-deficient HBV mutant was generated. Confocal microscopy, immune electron microscopy of ultrathin sections and isolation of MVBs revealed that filaments enter MVBs. Inhibition of MVB biogenesis by the small-molecule inhibitor U18666A or inhibition of ESCRT functionality by coexpression of transdominant negative mutants (Vps4A, Vps4B, and CHMP3) abolishes the release of filaments while the secretion of spheres is not affected. These data indicate that in contrast to spheres which are secreted via the secretory pathway, filaments are released via ESCRT/MVB pathway like infectious viral particles. IMPORTANCEThis study revises the current model describing the release of subviral particles by showing that in contrast to spheres, which are secreted via the secretory pathway, filaments are released via the ESCRT/MVB pathway like infectious viral particles. These data significantly contribute to a better understanding of the viral morphogenesis and might be helpful for the design of novel antiviral strategies.T he human hepatitis B virus (HBV) is a spherical particle, 42 nm in diameter, consisting of an outer envelope and an inner icosahedral nucleocapsid. The nucleocapsid is formed by the core protein and harbors the viral genomic DNA. The HBV genome encodes at least four different open reading frames, coding for the viral polymerase, the core and the e antigen (HBcAg and HBeAg), the regulatory X protein (HBx), and the three different surface proteins (HBsAg): the large HBV surface protein (LHBs), the middle surface protein (MHBs) and the small surface protein (SHBs) (1). LHBs encompasses the PreS1 domain, the PreS2 domain, and the S domain, MHBs consists of the PreS2 and the S domain, and SHBs contains the S domain. These surface proteins are not only constitutive components of the envelope of viral particles but also assemble to capsid-free subviral particles lacking any viral genome having the shape of spheres and filaments (2) that are secreted in 1,000-to 100,000-fold excess relative to infectious viral particles. SHBs, the predominant part of these subviral particles, can assemble to 22-nm spherical particles. The incorporation ...

show abstract

Nrf2

Kim

2017

Liver Pathophysiology

View full text Add to dashboard Cite

Intracellular accumulation of subviral HBsAg particles and diminished Nrf2 activation in HBV genotype G expressing cells lead to an increased ROI level

Cited by 37 publications

References 29 publications

Oxidative stress, a trigger of hepatitis C and B virus-induced liver carcinogenesis

Oxidative stress, a trigger of hepatitis C and B virus-induced liver carcinogenesis

Subviral Hepatitis B Virus Filaments, like Infectious Viral Particles, Are Released via Multivesicular Bodies

Nrf2

Contact Info

Product

Resources

About