Hepatitis C Virus nonstructural 5A protein inhibits lipopolysaccharide-mediated apoptosis of hepatocytes by decreasing expression of Toll-like receptor 4. 2011

Ryo Tamura, and Tatsuo Kanda, and Fumio Imazeki, and Shuang Wu, and Shingo Nakamoto, and Takeshi Tanaka, and Makoto Arai, and Keiichi Fujiwara, and Kengo Saito, and Thierry Roger, and Takaji Wakita, and Hiroshi Shirasawa, and Osamu Yokosuka
Department of Medicine and Clinical Oncology, Chiba University, Graduate School of Medicine, Japan.

BACKGROUND Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) has been shown to modulate multiple cellular processes, including apoptosis. The aim of this study was to assess the effects of HCV NS5A on apoptosis induced by Toll-like receptor (TLR) 4 ligand, lipopolysaccharide (LPS). METHODS Apoptotic responses to TLR4 ligands and the expression of molecules involved in TLR signaling pathways in human hepatocytes were examined with or without expression of HCV NS5A. RESULTS HCV NS5A protected HepG2 hepatocytes against LPS-induced apoptosis, an effect linked to reduced TLR4 expression. A similar downregulation of TLR4 expression was observed in Huh-7-expressing genotype 1b and 2a. In agreement with these findings, NS5A inhibited the expression of numerous genes encoding for molecules involved in TLR4 signaling, such as CD14, MD-2, myeloid differentiation primary response gene 88, interferon regulatory factor 3, and nuclear factor-κB2. Consistent with a conferred prosurvival advantage, NS5A diminished the poly(adenosine diphosphate-ribose) polymerase cleavage and the activation of caspases 3, 7, 8, and 9 and increased the expression of anti-apoptotic molecules Bcl-2 and c-FLIP. CONCLUSIONS HCV NS5A downregulates TLR4 signaling and LPS-induced apoptotic pathways in human hepatocytes, suggesting that disruption of TLR4-mediated apoptosis may play a role in the pathogenesis of HCV infection.

UI MeSH Term Description Entries
D008024 Ligands A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed) Ligand
D008070 Lipopolysaccharides Lipid-containing polysaccharides which are endotoxins and important group-specific antigens. They are often derived from the cell wall of gram-negative bacteria and induce immunoglobulin secretion. The lipopolysaccharide molecule consists of three parts: LIPID A, core polysaccharide, and O-specific chains (O ANTIGENS). When derived from Escherichia coli, lipopolysaccharides serve as polyclonal B-cell mitogens commonly used in laboratory immunology. (From Dorland, 28th ed) Lipopolysaccharide,Lipoglycans
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D005786 Gene Expression Regulation Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation. Gene Action Regulation,Regulation of Gene Expression,Expression Regulation, Gene,Regulation, Gene Action,Regulation, Gene Expression
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D015536 Down-Regulation A negative regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (GENE EXPRESSION REGULATION), mRNAs (RNA, MESSENGER), and proteins. Receptor Down-Regulation,Down-Regulation (Physiology),Downregulation,Down Regulation,Down-Regulation, Receptor
D016174 Hepacivirus A genus of FLAVIVIRIDAE causing parenterally-transmitted HEPATITIS C which is associated with transfusions and drug abuse. Hepatitis C virus is the type species. Hepatitis C virus,Hepatitis C-Like Viruses,Hepaciviruses,Hepatitis C Like Viruses,Hepatitis C viruses,Hepatitis C-Like Virus
D016328 NF-kappa B Ubiquitous, inducible, nuclear transcriptional activator that binds to enhancer elements in many different cell types and is activated by pathogenic stimuli. The NF-kappa B complex is a heterodimer composed of two DNA-binding subunits: NF-kappa B1 and relA. Immunoglobulin Enhancer-Binding Protein,NF-kappa B Complex,Nuclear Factor kappa B,Transcription Factor NF-kB,kappa B Enhancer Binding Protein,Ig-EBP-1,NF-kB,NF-kappaB,Nuclear Factor-Kappab,Complex, NF-kappa B,Enhancer-Binding Protein, Immunoglobulin,Factor NF-kB, Transcription,Factor-Kappab, Nuclear,Ig EBP 1,Immunoglobulin Enhancer Binding Protein,NF kB,NF kappa B Complex,NF kappaB,NF-kB, Transcription Factor,Nuclear Factor Kappab,Transcription Factor NF kB
D017209 Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, i.e., DNA FRAGMENTATION. It is genetically programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Apoptosis, Extrinsic Pathway,Apoptosis, Intrinsic Pathway,Caspase-Dependent Apoptosis,Classic Apoptosis,Classical Apoptosis,Programmed Cell Death,Programmed Cell Death, Type I,Apoptoses, Extrinsic Pathway,Apoptoses, Intrinsic Pathway,Apoptosis, Caspase-Dependent,Apoptosis, Classic,Apoptosis, Classical,Caspase Dependent Apoptosis,Cell Death, Programmed,Classic Apoptoses,Extrinsic Pathway Apoptoses,Extrinsic Pathway Apoptosis,Intrinsic Pathway Apoptoses,Intrinsic Pathway Apoptosis

Related Publications

Ryo Tamura, and Tatsuo Kanda, and Fumio Imazeki, and Shuang Wu, and Shingo Nakamoto, and Takeshi Tanaka, and Makoto Arai, and Keiichi Fujiwara, and Kengo Saito, and Thierry Roger, and Takaji Wakita, and Hiroshi Shirasawa, and Osamu Yokosuka
January 2014, PloS one,
Ryo Tamura, and Tatsuo Kanda, and Fumio Imazeki, and Shuang Wu, and Shingo Nakamoto, and Takeshi Tanaka, and Makoto Arai, and Keiichi Fujiwara, and Kengo Saito, and Thierry Roger, and Takaji Wakita, and Hiroshi Shirasawa, and Osamu Yokosuka
June 2003, Zhonghua nei ke za zhi,
Ryo Tamura, and Tatsuo Kanda, and Fumio Imazeki, and Shuang Wu, and Shingo Nakamoto, and Takeshi Tanaka, and Makoto Arai, and Keiichi Fujiwara, and Kengo Saito, and Thierry Roger, and Takaji Wakita, and Hiroshi Shirasawa, and Osamu Yokosuka
November 2003, The Journal of infectious diseases,
Ryo Tamura, and Tatsuo Kanda, and Fumio Imazeki, and Shuang Wu, and Shingo Nakamoto, and Takeshi Tanaka, and Makoto Arai, and Keiichi Fujiwara, and Kengo Saito, and Thierry Roger, and Takaji Wakita, and Hiroshi Shirasawa, and Osamu Yokosuka
January 2015, PloS one,
Ryo Tamura, and Tatsuo Kanda, and Fumio Imazeki, and Shuang Wu, and Shingo Nakamoto, and Takeshi Tanaka, and Makoto Arai, and Keiichi Fujiwara, and Kengo Saito, and Thierry Roger, and Takaji Wakita, and Hiroshi Shirasawa, and Osamu Yokosuka
May 2019, Oncology reports,
Ryo Tamura, and Tatsuo Kanda, and Fumio Imazeki, and Shuang Wu, and Shingo Nakamoto, and Takeshi Tanaka, and Makoto Arai, and Keiichi Fujiwara, and Kengo Saito, and Thierry Roger, and Takaji Wakita, and Hiroshi Shirasawa, and Osamu Yokosuka
January 2015, PloS one,
Ryo Tamura, and Tatsuo Kanda, and Fumio Imazeki, and Shuang Wu, and Shingo Nakamoto, and Takeshi Tanaka, and Makoto Arai, and Keiichi Fujiwara, and Kengo Saito, and Thierry Roger, and Takaji Wakita, and Hiroshi Shirasawa, and Osamu Yokosuka
September 2007, Journal of virology,
Ryo Tamura, and Tatsuo Kanda, and Fumio Imazeki, and Shuang Wu, and Shingo Nakamoto, and Takeshi Tanaka, and Makoto Arai, and Keiichi Fujiwara, and Kengo Saito, and Thierry Roger, and Takaji Wakita, and Hiroshi Shirasawa, and Osamu Yokosuka
June 2000, Journal of virology,
Ryo Tamura, and Tatsuo Kanda, and Fumio Imazeki, and Shuang Wu, and Shingo Nakamoto, and Takeshi Tanaka, and Makoto Arai, and Keiichi Fujiwara, and Kengo Saito, and Thierry Roger, and Takaji Wakita, and Hiroshi Shirasawa, and Osamu Yokosuka
January 2017, PloS one,
Ryo Tamura, and Tatsuo Kanda, and Fumio Imazeki, and Shuang Wu, and Shingo Nakamoto, and Takeshi Tanaka, and Makoto Arai, and Keiichi Fujiwara, and Kengo Saito, and Thierry Roger, and Takaji Wakita, and Hiroshi Shirasawa, and Osamu Yokosuka
June 2012, Hepatology (Baltimore, Md.),
Copied contents to your clipboard!