scholarly journals Hepatitis C virus modulates signal peptide peptidase to alter host protein processing

2021 ◽  
Vol 118 (22) ◽  
pp. e2026184118
Author(s):  
Junki Hirano ◽  
Sachiyo Yoshio ◽  
Yusuke Sakai ◽  
Li Songling ◽  
Tatsuya Suzuki ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antigen Presentation ◽  
Mhc Class I ◽  
Signal Peptide ◽  
Core Protein ◽  
Class I ◽  
Immune Recognition ◽  
Hcv Core Protein ◽  
Mhc Class I Molecules

Immunoevasins are viral proteins that prevent antigen presentation on major histocompatibility complex (MHC) class I, thus evading host immune recognition. Hepatitis C virus (HCV) evades immune surveillance to induce chronic infection; however, how HCV-infected hepatocytes affect immune cells and evade immune recognition remains unclear. Herein, we demonstrate that HCV core protein functions as an immunoevasin. Its expression interfered with the maturation of MHC class I molecules catalyzed by the signal peptide peptidase (SPP) and induced their degradation via HMG-CoA reductase degradation 1 homolog, thereby impairing antigen presentation to CD8+ T cells. The expression of MHC class I in the livers of HCV core transgenic mice and chronic hepatitis C patients was impaired but was restored in patients achieving sustained virological response. Finally, we show that the human cytomegalovirus US2 protein, possessing a transmembrane region structurally similar to the HCV core protein, targets SPP to impair MHC class I molecule expression. Thus, SPP represents a potential target for the impairment of MHC class I molecules by DNA and RNA viruses.

scholarly journals Amino Acid Polymorphisms in Hepatitis C Virus Core Affect Infectious Virus Production and Major Histocompatibility Complex Class I Molecule Expression

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Megumi Tasaka-Fujita ◽  
Nao Sugiyama ◽  
Wonseok Kang ◽  
Takahiro Masaki ◽  
Asako Murayama ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Amino Acid ◽  
Mhc Class I ◽  
Infectious Virus ◽  
Core Protein ◽  
Virus Production ◽  
Class I ◽  
Histocompatibility Complex

Abstract Amino acid (aa) polymorphisms in the hepatitis C virus (HCV) genotype 1b core protein have been reported to be a potent predictor for poor response to interferon (IFN)-based therapy and a risk factor for hepatocarcinogenesis. We investigated the effects of these polymorphisms with genotype 1b/2a chimeric viruses that contained polymorphisms of Arg/Gln at aa 70 and Leu/Met at aa 91. We found that infectious virus production was reduced in cells transfected with chimeric virus RNA that had Gln at aa 70 (aa70Q) compared with RNA with Arg at aa 70 (aa70R). Using flow cytometry analysis, we confirmed that HCV core protein accumulated in aa70Q clone transfected cells and it caused a reduction in cell-surface expression of major histocompatibility complex (MHC) class I molecules induced by IFN treatment through enhanced protein kinase R phosphorylation. We could not detect any effects due to the polymorphism at aa 91. In conclusion, the polymorphism at aa 70 was associated with efficiency of infectious virus production and this deteriorated virus production in strains with aa70Q resulted in the intracellular accumulation of HCV proteins and attenuation of MHC class I molecule expression. These observations may explain the strain-associated resistance to IFN-based therapy and hepatocarcinogenesis of HCV.

scholarly journals Efficient cleavage by signal peptide peptidase requires residues within the signal peptide between the core and E1 proteins of hepatitis C virus strain J1

2006 ◽  
Vol 87 (3) ◽  
pp. 623-627 ◽  
Author(s):  
R. Graham Hope ◽  
Marion J. McElwee ◽  
John McLauchlan
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Signal Peptide ◽  
Core Protein ◽  
Signal Peptidase ◽  
Wild Type ◽  
Signal Peptide Peptidase ◽  
Standard Buffer ◽  
Hcv Core Protein ◽  
Mutant Forms

Maturation of hepatitis C virus (HCV) core protein requires cleavage by signal peptidase (SP) and signal peptide peptidase (SPP) at a signal peptide between core and the E1 glycoprotein. For HCV strain Glasgow, amino acids Ala180, Ser183 and Cys184 within the signal peptide have previously been shown to be essential for efficient SPP cleavage. By contrast, these residues apparently did not contribute to core maturation in HCV strain J1. In the present study, the source of this discrepancy has been analysed and it is concluded that interpretation of the strain J1 data was incorrect, due to the inability to separate wild-type and mutant forms of core on gels by using standard buffer systems.

scholarly journals Intramembrane Processing by Signal Peptide Peptidase Regulates the Membrane Localization of Hepatitis C Virus Core Protein and Viral Propagation

2008 ◽  
Vol 82 (17) ◽  
pp. 8349-8361 ◽  
Author(s):  
Kiyoko Okamoto ◽  
Yoshio Mori ◽  
Yasumasa Komoda ◽  
Toru Okamoto ◽  
Masayasu Okochi ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Signal Peptide ◽  
Core Protein ◽  
Biological Significance ◽  
Signal Peptidase ◽  
Signal Peptide Peptidase ◽  
Viral Propagation ◽  
The Core ◽  
Hcv Core Protein

ABSTRACT Hepatitis C virus (HCV) core protein has shown to be localized in the detergent-resistant membrane (DRM), which is distinct from the classical raft fraction including caveolin, although the biological significance of the DRM localization of the core protein has not been determined. The HCV core protein is cleaved off from a precursor polyprotein at the lumen side of Ala191 by signal peptidase and is then further processed by signal peptide peptidase (SPP) within the transmembrane region. In this study, we examined the role of SPP in the localization of the HCV core protein in the DRM and in viral propagation. The C terminus of the HCV core protein cleaved by SPP in 293T cells was identified as Phe177 by mass spectrometry. Mutations introduced into two residues (Ile176 and Phe177) upstream of the cleavage site of the core protein abrogated processing by SPP and localization in the DRM fraction. Expression of a dominant-negative SPP or treatment with an SPP inhibitor, L685,458, resulted in reductions in the levels of processed core protein localized in the DRM fraction. The production of HCV RNA in cells persistently infected with strain JFH-1 was impaired by treatment with the SPP inhibitor. Furthermore, mutant JFH-1 viruses bearing SPP-resistant mutations in the core protein failed to propagate in a permissive cell line. These results suggest that intramembrane processing of HCV core protein by SPP is required for the localization of the HCV core protein in the DRM and for viral propagation.

scholarly journals Characterization of Hepatitis C Virus Core Protein Multimerization and Membrane Envelopment: Revelation of a Cascade of Core-Membrane Interactions

2009 ◽  
Vol 83 (19) ◽  
pp. 9923-9939 ◽  
Author(s):  
Li-Shuang Ai ◽  
Yu-Wen Lee ◽  
Steve S.-L. Chen
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Complex Formation ◽  
Signal Peptide ◽  
Core Protein ◽  
The Core ◽  
Hcv Core Protein ◽  
Core Proteins ◽  
Multimeric Complex ◽  
Protein Multimerization

ABSTRACT The molecular basis underlying hepatitis C virus (HCV) core protein maturation and morphogenesis remains elusive. We characterized the concerted events associated with core protein multimerization and interaction with membranes. Analyses of core proteins expressed from a subgenomic system showed that the signal sequence located between the core and envelope glycoprotein E1 is critical for core association with endoplasmic reticula (ER)/late endosomes and the core's envelopment by membranes, which was judged by the core's acquisition of resistance to proteinase K digestion. Despite exerting an inhibitory effect on the core's association with membranes, (Z-LL)2-ketone, a specific inhibitor of signal peptide peptidase (SPP), did not affect core multimeric complex formation, suggesting that oligomeric core complex formation proceeds prior to or upon core attachment to membranes. Protease-resistant core complexes that contained both innate and processed proteins were detected in the presence of (Z-LL)2-ketone, implying that core envelopment occurs after intramembrane cleavage. Mutations of the core that prevent signal peptide cleavage or coexpression with an SPP loss-of-function D219A mutant decreased the core's envelopment, demonstrating that SPP-mediated cleavage is required for core envelopment. Analyses of core mutants with a deletion in domain I revealed that this domain contains sequences crucial for core envelopment. The core proteins expressed by infectious JFH1 and Jc1 RNAs in Huh7 cells also assembled into a multimeric complex, associated with ER/late-endosomal membranes, and were enveloped by membranes. Treatment with (Z-LL)2-ketone or coexpression with D219A mutant SPP interfered with both core envelopment and infectious HCV production, indicating a critical role of core envelopment in HCV morphogenesis. The results provide mechanistic insights into the sequential and coordinated processes during the association of the HCV core protein with membranes in the early phase of virus maturation and morphogenesis.

scholarly journals Upregulation of Major Histocompatibility Complex Class I on Liver Cells by Hepatitis C Virus Core Protein via p53 and TAP1 Impairs Natural Killer Cell Cytotoxicity

2003 ◽  
Vol 77 (15) ◽  
pp. 8299-8309 ◽  
Author(s):  
Kerstin Herzer ◽  
Christine S. Falk ◽  
Jens Encke ◽  
Sören T. Eichhorst ◽  
Axel Ulsenheimer ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Chronic Infection ◽  
Core Protein ◽  
Class I ◽  
Histocompatibility Complex

ABSTRACT The mechanisms of immune evasion and the role of the early immune response in chronic infection caused by hepatitis C virus (HCV) are still unclear. Here, we present evidence for a cascade of molecular events that the virus initiates to subvert the innate immune attack. The HCV core protein induced p53-dependent gene expression of TAP1 (transporter associated with antigen processing 1) and consecutive major histocompatibility complex (MHC) class I upregulation. Moreover, in p53-deficient liver cell lines, only reconstitution with wild-type p53, but not mutated p53 lacking DNA binding capacity, showed this effect. As a consequence of increased MHC class I expression, a significantly downregulated cytotoxic activity of natural killer (NK) cells against HCV core-transfected liver cells was observed, whereas lysis by HCV-specific cytotoxic T cells was not affected. These results demonstrate a way in which HCV avoids recognition by NK cells that may contribute to the establishment of a chronic infection.

scholarly journals Core protein cleavage by signal peptide peptidase is required for hepatitis C virus-like particle assembly

2006 ◽  
Vol 87 (4) ◽  
pp. 855-860 ◽  
Author(s):  
Malika Ait-Goughoulte ◽  
Christophe Hourioux ◽  
Romuald Patient ◽  
Sylvie Trassard ◽  
Denys Brand ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Signal Peptide ◽  
Semliki Forest Virus ◽  
Core Protein ◽  
Protein Cleavage ◽  
Particle Assembly ◽  
Signal Peptide Peptidase ◽  
Hcv Core Protein ◽  
Er Membrane

Hepatitis C virus (HCV) core protein, expressed with a Semliki Forest virus replicon, self-assembles into HCV-like particles (HCV-LP) at the endoplasmic reticulum (ER) membrane, providing an opportunity to study HCV assembly and morphogenesis by electron microscopy. This model was used to investigate whether the processing of the HCV core protein by the signal peptide peptidase (SPP) is required for the HCV-LP assembly. Several mutants were designed as there are conflicting reports concerning the cleavage of mutant proteins by SPP. Production of the only core mutant protein that escaped SPP processing led to the formation of multiple layers of electron-dense ER membrane, with no evidence of HCV-LP assembly. These data shed light on the HCV core residues involved in SPP cleavage and suggest that this cleavage is essential for HCV assembly.

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