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

Okamoto, Kazuhira; Moriishi, Kohji; Miyamura, Tatsuo; Matsuura, Yoshiharu

doi:10.1128/jvi.78.12.6370-6380.2004

Cited by 91 publications

(110 citation statements)

References 55 publications

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“…As the processing protease, the novel aspartic proteinase SPP has been proposed (20). Important evidence for this finding came from the use of (Z-LL) 2 -ketone and the expression of a dominant-negative mutant of SPP (9). In either case the action of SPP was inhibited.…”

Section: Resultsmentioning

confidence: 99%

“…All proposed C termini of HCV core protein locate within the central hydrophobic domain of the signal peptide that conducts the translocation of E1 to the endoplasmic reticulum (4). Evidence for the involvement of the intramembrane proteinase SPP in the processing of HCV core protein came from inhibitor studies using peptidomimetic (carboxybenzoyl-Leu-Leu) 2 -ketone [(Z-LL) 2 -ketone] and overexpression of the SPP D 219 A lossof-function mutant (9,20). Analysis of the SPP cleavage site revealed that helix-breaking or -bending residues are a prerequisite for SPP cleavage to occur.…”

mentioning

confidence: 99%

“…Analysis of the SPP cleavage site revealed that helix-breaking or -bending residues are a prerequisite for SPP cleavage to occur. These residues were identified in the HCV sequence by site-directed mutagenesis of either Ser 183 Cys 184 (7) or Ile 175 Phe 176 (9). SPP is an aspartyl protease of the GXGD type and is related to presenilin (20).…”

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confidence: 99%

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Core Protein of Pestiviruses Is Processed at the C Terminus by Signal Peptide Peptidase

Heimann

Sosa

Martoglio

et al. 2006

J Virol

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The core protein of pestiviruses is released from the polyprotein by viral and cellular proteinases. Here we report on an additional intramembrane proteolytic step that generates the C terminus of the core protein. C-terminal processing of the core protein of classical swine fever virus (CSFV) was blocked by the inhibitor (Z-LL) 2 -ketone, which is specific for signal peptide peptidase (SPP). The same effect was obtained by overexpression of the dominant-negative SPP D 265 A mutant. The presence of (Z-LL) 2 -ketone reduced the viability of CSFV almost 100-fold in a concentration-dependent manner. Reduction of virus viability was also observed in infection experiments using a cell line that inducibly expressed SPP D 265 A. The position of SPP cleavage was determined by C-terminal sequencing of core protein purified from virions. The C terminus of CSFV core protein is alanine 255 and is located in the hydrophobic center of the signal peptide. The intramembrane generation of the C terminus of the CSFV core protein is almost identical to the processing scheme of the core protein of hepatitis C viruses.Pestiviruses are small, enveloped RNA viruses that account for important diseases in farm animals, e.g., classical swine fever (also known as hog cholera) and bovine viral diarrhea. Pestiviruses constitute one genus within the Flaviviridae and contain a message sense RNA of about 12.3 kilobases. The genome is translated into a single polyprotein that is processed by cellular and viral proteases into 12 mature proteins. The virion consists of four structural proteins, the core protein and the glycoproteins E rns , E1, and E2 (19). The core protein of all members of the Flaviviridae is a small protein rich in basic amino acids and locates at or near the N terminus of the polyprotein (11). In the pestivirus polyprotein, the core protein is located between the N-terminal protease N pro and the glycoprotein E rns . N pro generates the N terminus (Ser 169 ) of the core protein by autocatalytic cleavage of the polyprotein (15, 18). Core protein is followed by E rns , whose N terminus (Asp 268 ) is generated by signal peptidase (signalase, or SP) (16).Two different mechanisms of release of core protein from the polyprotein have been described for members of the Flaviviridae. Members of the genus Flavivirus (e.g., yellow fever virus [YFV]) employ the virally encoded NS2B-3 protease to generate the C terminus of core protein. The NS2B-3 protease of YFV cleaves the core protein precursor at a tribasic consensus sequence at the N terminus of the preM signal peptide (1). For hepatitis C virus (HCV), signal peptide peptidase (SPP) was recently determined to cleave within the C-terminal domain of core protein (7). Thus far, three different C termini have been proposed for HCV core protein. N-terminal sequencing of HCV core-dihydrofolate reductase fusion proteins revealed cleavage after Leu 179 or Leu 182 (4). In a recent report, Phe 177 was identified as the C terminus of HCV core protein by using matrix-assisted laser desorption ion...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Core Protein of Pestiviruses Is Processed at the C Terminus by Signal Peptide Peptidase

Heimann

Sosa

Martoglio

et al. 2006

J Virol

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“…Evidences have shown that ER stress occurs in nearly all physiologies related to acute and chronic liver disease including alcoholic liver disease, 29,30) nonalcoholic fatty liver disease, 31) viral hepatitis, 32,33) and drug-induced liver injury (DILI). [34][35][36] The ER plays a crucial role in maintaining cellular homeostasis, regulating protein synthesis, Ca 2+ transportation and drug metabolism.…”

Section: Discussionmentioning

confidence: 99%

Bavachin Induces Apoptosis through Mitochondrial Regulated ER Stress Pathway in HepG2 Cells

Yang

Tang²,

Hao³

et al. 2018

Biological & Pharmaceutical Bulletin

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As a traditional herbal medicine, the fruits of Psoralea corylifolia L. (Fructus Psoraleae (FP)) have been widely used for the treatment of various skin diseases for hundred years. Recently, the emerging FPinduced toxic effects, especially hepatotoxicity, in clinic are getting the public's attention. However, its exact toxic components and mechanisms underlying remain unclear. Bavachin, one of flavonoids in FP, has been documented as a hepatotoxic substance, and the present study aimed to determine the toxicity caused by bavachin and the possible toxic mechanisms involved using human hepatocellular carcinoma (HepG2) cells. Our results showed that bavachin could significantly inhibited cell proliferation and trigger the endoplasmic reticulum (ER) stress in a dose dependent manner. Downregulating ER stress using tauroursodeoxycholic acid (TUDCA) obvious attenuated bavachin-triggerd cell apoptosis. Then, small interfering RNA (siRNA) knock-down of Mitofusion2 (Mfn2) resulted in a remarkable aggravation of ER stress through the inhibition of the phosphorylation of protein kinase B (Akt). Additionally, suppression of reactive oxygen species (ROS) by ROS Scavenger (N-acetyl-l-cystein (NAC)) also reduced bavachin-induced ER stress. Taken together, our study demonstrated that bavachin-induced ER stress caused cell apoptosis by Mfn2-Akt pathway, and that ROS may participate upstream in this mechanism. Here, we not only provide a new understanding of ROS/ Mfn2/Akt pathway in bavachin-induced cytotoxicity via the ER stress, but also identify a new specific intervention to prevent FP-induced hepatotoxicity in the future.

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“…22 Studies by others have demonstrated that the HCV core protein 1 is cleaved by signal peptidases between residues 191 and 192 to generate the retained E1 envelope. 23,24 PHC09 contains 10 amino acids (SAIHIRNASG). The major (8 amino acids) molecular mimicry sequence (IHIRNASG) is located in the retained HCV 1 envelope region, which is likely to retain the epitope specificity.…”

Section: Discussionmentioning

confidence: 99%

Role of molecular mimicry of hepatitis C virus protein with platelet GPIIIa in hepatitis C–related immunologic thrombocytopenia

Zhang¹,

Nardi

Borkowsky

et al. 2009

Blood

132

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

Abstract: Hepatitis C virus (HCV) core protein is suggested to localize to the endoplasmic reticulum (ER) through

Cited by 91 publications

References 55 publications

Core Protein of Pestiviruses Is Processed at the C Terminus by Signal Peptide Peptidase

Core Protein of Pestiviruses Is Processed at the C Terminus by Signal Peptide Peptidase

Bavachin Induces Apoptosis through Mitochondrial Regulated ER Stress Pathway in HepG2 Cells

Role of molecular mimicry of hepatitis C virus protein with platelet GPIIIa in hepatitis C–related immunologic thrombocytopenia

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