Sequence motifs required for lipid droplet association and protein stability are unique to the hepatitis C virus core protein

Hope, RM; McLauchlan, John

doi:10.1099/0022-1317-81-8-1913

Cited by 200 publications

(229 citation statements)

References 47 publications

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“…However, the precise functions of HCV proteins in the development of fatty liver remain unknown because of the lack of a system sufficient to investigate the pathogenesis of HCV. HCV core protein expression has been shown to induce lipid droplets in cell lines and hepatic steatosis and HCC in transgenic mice (4)(5)(6). These reports suggest that HCV core protein plays an important role in the development of various types of liver failure, including steatosis and HCC.…”

mentioning

confidence: 85%

Critical role of PA28γ in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis

Moriishi

Mochizuki

Moriya

et al. 2007

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

192

196

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Hepatitis C virus (HCV) is a major cause of chronic liver disease that frequently leads to steatosis, cirrhosis, and eventually hepatocellular carcinoma (HCC). HCV core protein is not only a component of viral particles but also a multifunctional protein because liver steatosis and HCC are developed in HCV core gene-transgenic (CoreTg) mice. Proteasome activator PA28␥/REG␥ regulates host and viral proteins such as nuclear hormone receptors and HCV core protein. Here we show that a knockout of the PA28␥ gene induces the accumulation of HCV core protein in the nucleus of hepatocytes of CoreTg mice and disrupts development of both hepatic steatosis and HCC. Furthermore, the genes related to fatty acid biosynthesis and srebp-1c promoter activity were up-regulated by HCV core protein in the cell line and the mouse liver in a PA28␥-dependent manner. Heterodimer composed of liver X receptor ␣ (LXR␣) and retinoid X receptor ␣ (RXR␣) is known to up-regulate srebp-1c promoter activity. Our data also show that HCV core protein enhances the binding of LXR␣/RXR␣ to LXR-response element in the presence but not the absence of PA28␥. These findings suggest that PA28␥ plays a crucial role in the development of liver pathology induced by HCV infection.fatty acid ͉ proteasome ͉ sterol regulatory element-binding protein (SREBP) ͉ RXR␣ ͉ LXR␣ H epatitis C virus (HCV) belongs to the Flaviviridae family, and it possesses a positive, single-stranded RNA genome that encodes a single polyprotein composed of Ϸ3,000 aa. The HCV polyprotein is processed by host and viral proteases, resulting in 10 viral proteins. Viral structural proteins, including the capsid (core) protein and two envelope proteins, are located in the N-terminal one-third of the polyprotein, followed by nonstructural proteins.HCV infects Ͼ170 million individuals worldwide, and then it causes liver disease, including hepatic steatosis, cirrhosis, and eventually hepatocellular carcinoma (HCC) (1). The prevalence of fatty infiltration in the livers of chronic hepatitis C patients has been reported to average Ϸ50% (2, 3), which is higher than the percentage in patients infected with hepatitis B virus and other liver diseases. However, the precise functions of HCV proteins in the development of fatty liver remain unknown because of the lack of a system sufficient to investigate the pathogenesis of HCV. HCV core protein expression has been shown to induce lipid droplets in cell lines and hepatic steatosis and HCC in transgenic mice (4-6). These reports suggest that HCV core protein plays an important role in the development of various types of liver failure, including steatosis and HCC.Recent reports suggest that lipid biosynthesis affects HCV replication (7-9). Involvement of a geranylgeranylated host protein, FBL2, in HCV replication through the interaction with NS5A suggests that the cholesterol biosynthesis pathway is also important for HCV replication (9). Increases in saturated and monounsaturated fatty acids enhance HCV RNA replication, whereas increases in polyunsaturat...

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mentioning

confidence: 85%

Critical role of PA28γ in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis

Moriishi

Mochizuki

Moriya

et al. 2007

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

192

196

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“…Domain 2 was hypothesized to interact with lipid droplets and confer stability to the HCV core protein (12). Although a mutation in the signal sequence of core protein that renders it resistant to SPP proteolysis restored retention on lipid droplets and overall stability (30), deletion of domain 2 from HCV core protein leads to diffusion in the cytoplasm and degradation after processing by signal peptidase (30).…”

Section: Discussionmentioning

confidence: 99%

Intramembrane Proteolysis and Endoplasmic Reticulum Retention of Hepatitis C Virus Core Protein

Okamoto

Moriishi

Miyamura

et al. 2004

J Virol

101

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“…Association of HCV core protein with lipid droplets requires a domain of about 55 amino acids that is present also in a related virus, GB virus-B but not in pesti-and flaviviruses that share the same genomic organization as HCV (11,12). Apart from a short stretch of amino acids, removal or substitution of amino acids along the length of the domain abolishes lipid droplet localization.…”

Section: Adrp Does Not Diffuse Rapidly Between Adjacent Lipidmentioning

confidence: 99%

“…Lipid droplets were stained with oil red O (Sigma) in paraformaldehyde-fixed cells as described previously (11,12). For staining of lipid droplets with Bodipy 558/568 C 12 (Molecular Probes Europe BV, The Netherlands), cells were incubated with the dye at a final concentration of 20 g/ml for 45 min at 37°C in PBS, rinsed to remove excess stain followed by a further incubation of 60 min at 37°C in cell culture media.…”

Section: Generation Of Human Andmentioning

confidence: 99%

Live Cell Analysis and Targeting of the Lipid Droplet-binding Adipocyte Differentiation-related Protein

Targett-Adams¹,

Chambers

Gledhill

et al. 2003

Journal of Biological Chemistry

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185

181

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Neutral lipid is stored in spherical organelles called lipid droplets that are bounded by a coat of proteins. The protein that is most frequently found at the surface of lipid droplets is adipocyte differentiation-related protein (ADRP). In this study, we demonstrate that fusion of either the human or mouse ADRP coding sequences to green fluorescent protein (GFP) does not disrupt the ability of the protein to associate with lipid droplets. Using this system to identify targeting elements, discontinuous segments within the coding region were required for directing ADRP to lipid droplets. GFP-tagged protein was employed also to examine the behavior of lipid droplets in live cells. Time lapse microscopy demonstrated that in HuH-7 cells, which are derived from a human hepatoma, a small number of lipid droplets could move rapidly, indicating transient association with intracellular transport pathways. Most lipid droplets did not show such movement but oscillated within a confined area; these droplets were in close association with the endoplasmic reticulum membrane and moved in concert with the endoplasmic reticulum. Fluorescence recovery analysis of GFP-tagged ADRP in live cells revealed that surface proteins do not rapidly diffuse between lipid droplets, even in conditions where they are closely packed. This system provides new insights into the properties of lipid droplets and their interaction with cellular processes.

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Sequence motifs required for lipid droplet association and protein stability are unique to the hepatitis C virus core protein

Cited by 200 publications

References 47 publications

Critical role of PA28γ in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis

Critical role of PA28γ in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis

Intramembrane Proteolysis and Endoplasmic Reticulum Retention of Hepatitis C Virus Core Protein

Live Cell Analysis and Targeting of the Lipid Droplet-binding Adipocyte Differentiation-related Protein

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