Hepatitis C virus NS4B induces unfolded protein response and endoplasmic reticulum overload response-dependent NF-κB activation

Li, Shanshan; Ye, Linbai; Yu, Xilan; Xu, Bin; Li, Kun-tai; Zhu, Xiangzhen; Liu, Haoju; Wu, Xiaoyu; Kong, Lingbao

doi:10.1016/j.virol.2009.06.039

Cited by 123 publications

(115 citation statements)

References 39 publications

Supporting

Mentioning

111

Contrasting

Unclassified

Order By: Relevance

“…Indeed, there are contradictory reports on the requirement for Ire1p in the ER expansion induced by membrane proteins in yeast (2,(9)(10)(11). In mammals, membrane protein overexpression can induce the UPR (7,12), but a causal relationship between UPR signaling and membrane protein-induced ER expansion has not been established. In addition, a high load of membrane proteins, such as that caused by many viral infections or transient transfections, can drive both the UPR and activation of the transcription factor NF-κB (12,13).…”

mentioning

confidence: 99%

“…In mammals, membrane protein overexpression can induce the UPR (7,12), but a causal relationship between UPR signaling and membrane protein-induced ER expansion has not been established. In addition, a high load of membrane proteins, such as that caused by many viral infections or transient transfections, can drive both the UPR and activation of the transcription factor NF-κB (12,13). The latter response, known as the ER overload response, depends both on Ca 2+ leakage from the ER lumen and on reactive oxygen species (ROS) and may represent a cellular defense mechanism rather than a signaling pathway causally linked to membrane proliferation.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Selective activation of the transcription factor ATF6 mediates endoplasmic reticulum proliferation triggered by a membrane protein

Maiuolo

Bulotta

Verderio

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

It is well known that the endoplasmic reticulum (ER) is capable of expanding its surface area in response both to cargo load and to increased expression of resident membrane proteins. Although the response to increased cargo load, known as the unfolded protein response (UPR), is well characterized, the mechanism of the response to membrane protein load has been unclear. As a model system to investigate this phenomenon, we have used a HeLa-TetOff cell line inducibly expressing a tail-anchored construct consisting of an Nterminal cytosolic GFP moiety anchored to the ER membrane by the tail of cytochrome b5 [GFP-b(5)tail]. After removal of doxycycline, GFP-b(5)tail is expressed at moderate levels (1-2% of total ER protein) that, nevertheless, induce ER proliferation, as assessed both by EM and by a three-to fourfold increase in phosphatidylcholine synthesis. We investigated possible participation of each of the three arms of the UPR and found that only the activating transcription factor 6 (ATF6) arm was selectively activated after induction of GFPb(5)tail expression; peak ATF6α activation preceded the increase in phosphatidylcholine synthesis. Surprisingly, up-regulation of known ATF6 target genes was not observed under these conditions. Silencing of ATF6α abolished the ER proliferation response, whereas knockdown of Ire1 was without effect. Because GFP-b(5)tail lacks a luminal domain, the response we observe is unlikely to originate from the ER lumen. Instead, we propose that a sensing mechanism operates within the lipid bilayer to trigger the selective activation of ATF6.phospholipid biosynthesis | tail-anchored proteins | membrane biogenesis C ells are capable of adjusting the dimensions, architecture, and molecular composition of their organelles to changing functional needs. The endoplasmic reticulum (ER) offers a well-studied example of such organelle plasticity. When exposed to altered conditions, it initiates signaling cascades that result in the adjustment of its size and composition to the new situation. Among these signaling pathways, the one triggered by increased demand on the lumenal folding machinery, known as the unfolded protein response (UPR), plays a prominent role and has been extensively investigated (1).In yeast, the UPR is mediated by the ER transmembrane kinase/ endonuclease Ire1p, whereas in mammalian cells, the pathway has evolved to a higher degree of complexity, with the participation of two additional transmembrane sensors: the basic leucine zipper (bZIP) transcriptional regulator activating transcription factor 6α/ β (ATF6α/β) and the PKR-like ER kinase (PERK) (1). In the presence of unfolded proteins in the ER lumen, the three sensors induce changes in the activity of the transcriptional and translational apparatus that alleviate ER stress by (i) increasing the capacity of the lumenal folding machinery; (ii) enhancing ER-associated degradation; (iii) diminishing delivery of newly synthesized proteins to the ER lumen; and (iv) increasing phospholipid synthesis, with a resulting expans...

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

Selective activation of the transcription factor ATF6 mediates endoplasmic reticulum proliferation triggered by a membrane protein

Maiuolo

Bulotta

Verderio

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Xbp1s is a key regulator in the IRE1a signaling pathway of the unfolded protein response (UPR), which is activated by ER stress. Hepatic ER stress occurs due to insulin resistance, diabetes, obesity, and several liver diseases, including fatty liver, hepatitis C, and alpha-1 antitrypsin deficiency (Ji 2008;Lawless et al 2004;Li et al 2009;Puri et al 2008;Malhi and Kaufman 2011). In addition to its role in the UPR, hepatic Xbp1s is an important regulator of fatty acid synthesis and systemic lipid metabolism Sha et al 2009;Ye et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Identification of eQTLs for hepatic Xbp1 s and Socs3 gene expression in mice fed a high-fat, high caloric diet

Pasricha¹,

Anderson²,

Hall

et al. 2015

Z Gastroenterol

View full text Add to dashboard Cite

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent form of human hepatic disease and feeding mice a high-fat, high-caloric (HFHC) diet is a standard model of NAFLD. To better understand the genetic basis of NAFLD, we conducted an expression quantitative trait locus (eQTL) analysis of mice fed a HFHC diet. Two-hundred sixty-five (A/J · C57BL/6J) F 2 male mice were fed a HFHC diet for 8 wk. eQTL analysis was utilized to identify genomic regions that regulate hepatic gene expression of Xbp1s and Socs3. We identified two overlapping loci for Xbp1s and Socs3 on Chr 1 (164.0-185.4 Mb and 174.4-190.5 Mb, respectively) and Chr 11 (41.1-73.1 Mb and 44.0-68.6 Mb, respectively), and an additional locus for Socs3 on Chr 12 (109.9-117.4 Mb). C57BL/6J-Chr 11 A/J / NaJ mice fed a HFHC diet manifested the A/J phenotype of increased Xbp1s and Socs3 gene expression (P , 0.05), whereas C57BL/6J-Chr 1 A/J / NaJ mice retained the C57BL/6J phenotype. In addition, we replicated the eQTLs on Chr 1 and Chr 12 (LOD scores $3.5) using mice from the BXD murine reference panel challenged with CCl 4 to induce chronic liver injury and fibrosis. We have identified overlapping eQTLs for Xbp1 and Socs3 on Chr 1 and Chr 11, and consomic mice confirmed that replacing the C57BL/6J Chr 11 with the A/J Chr 11 resulted in an A/J phenotype for Xbp1 and Socs3 gene expression. Identification of the genes for these eQTLs will lead to a better understanding of the genetic factors responsible for NAFLD and potentially other hepatic diseases.

show abstract

“…core, E1, E2, NS3/4A, NS4B, and NS5A) (5), with core being the most potent inducer (10,11). Several mechanisms have been identified by which HCV infection can lead to the induction of ROS/RNS, including mitochondrial alterations (12)(13)(14)(15)(16); redistribution of calcium between the ER, cytoplasm, and mitochondria (17)(18)(19)(20)(21)(22)(23); increased expression of NADPH oxidases (24,25); enhanced expression of CYP2E1 (26 -29); as well as ER stress and the unfolded protein response (10,18,22,30,31). Oxidative stress also impacts the HCV life cycle at the level of replication and translation and can lead to viral genome heterogeneity, possibly facilitating viral escape from immune detection (32)(33)(34)(35)(36).…”

mentioning

confidence: 99%

Oxidative Stress Attenuates Lipid Synthesis and Increases Mitochondrial Fatty Acid Oxidation in Hepatoma Cells Infected with Hepatitis C Virus

Douglas

Lewis

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Cytopathic effects are currently believed to contribute to hepatitis C virus (HCV)-induced liver injury and are readily observed in Huh7.5 cells infected with the JFH-1 HCV strain, manifesting as apoptosis highly correlated with growth arrest. Reactive oxygen species, which are induced by HCV infection, have recently emerged as activators of AMP-activated protein kinase. The net effect is ATP conservation via on/off switching of metabolic pathways that produce/consume ATP. Depending on the scenario, this can have either pro-survival or pro-apoptotic effects. We demonstrate reactive oxygen species-mediated activation of AMP-activated kinase in Huh7.5 cells during HCV (JFH-1)-induced growth arrest. Metabolic labeling experiments provided direct evidence that lipid synthesis is attenuated, and ␤-oxidation is enhanced in these cells. A striking increase in nuclear peroxisome proliferator-activated receptor ␣, which plays a dominant role in the expression of ␤-oxidation genes after ligand-induced activation, was also observed, and we provide evidence that peroxisome proliferator-activated receptor ␣ is constitutively activated in these cells. The combination of attenuated lipid synthesis and enhanced ␤-oxidation is not conducive to lipid accumulation, yet cellular lipids still accumulated during this stage of infection. Notably, the serum in the culture media was the only available source for polyunsaturated fatty acids, which were elevated (2-fold) in the infected cells, implicating altered lipid import/export pathways in these cells. This study also provided the first in vivo evidence for enhanced ␤-oxidation during HCV infection because HCV-infected SCID/Alb-uPA mice accumulated higher plasma ketones while fasting than did control mice. Overall, this study highlights the reprogramming of hepatocellular lipid metabolism and bioenergetics during HCV infection, which are predicted to impact both the HCV life cycle and pathogenesis.With ϳ200 million people infected worldwide, hepatitis C virus (HCV) 2 is a global health problem and a major cause of viral hepatitis. Persistent infection occurs in ϳ70% of infected patients leading to inflammation, insulin resistance, steatosis, fibrosis, and hepatocellular carcinoma (1). Current direct-acting antivirals are predicted to be a cure for most patients, but the high cost of this treatment means that the pathological consequences of persistent HCV infection will remain a concern.Although the pathology associated with chronic HCV infection was initially thought to be due to HCV-specific immune responses (2), the current opinion is that direct cytopathic effects in virally infected cells also contribute to HCV-associated liver injury (3, 4). The cellular mechanisms by which HCV replication might mediate liver injury are unclear, but there is no doubt that oxidative/nitrosative stress in HCV-infected cells plays an important role in the initiation and progression of liver damage (3, 5, 6). Oxidative/nitrosative stress essentially arises when the production of reactive oxygen (...

show abstract

Hepatitis C virus NS4B induces unfolded protein response and endoplasmic reticulum overload response-dependent NF-κB activation

Cited by 123 publications

References 39 publications

Selective activation of the transcription factor ATF6 mediates endoplasmic reticulum proliferation triggered by a membrane protein

Selective activation of the transcription factor ATF6 mediates endoplasmic reticulum proliferation triggered by a membrane protein

Identification of eQTLs for hepatic Xbp1 s and Socs3 gene expression in mice fed a high-fat, high caloric diet

Oxidative Stress Attenuates Lipid Synthesis and Increases Mitochondrial Fatty Acid Oxidation in Hepatoma Cells Infected with Hepatitis C Virus

Contact Info

Product

Resources

About