Envelope glycoprotein E1
The transmembrane regions of envelope E1 and E2 glycoproteins are involved in heterodimer formation, ER localization, and assembly of these proteins.
Envelope glycoprotein E2
The transmembrane regions of envelope E1 and E2 glycoproteins are involved in heterodimer formation, ER localization, and assembly of these proteins (By similarity). Envelope E2 glycoprotein contain two highly variable regions called hypervariable region 1 and 2 (HVR1 and HVR2) (By similarity). E2 also contain two segments involved in CD81-binding (PubMed:12660945). HVR1 is implicated in the SCARB1-mediated cell entry and probably acts as a regulator of the association of particles with lipids (By similarity).
Protease NS2
The N-terminus of NS3 is required for the catalytic activity of protease NS2 (PubMed:11591719, PubMed:9261354). The minimal catalytic region includes the C-terminus of NS2 and the N-terminus NS3 protease domain (active region NS2-3) (PubMed:11591719).
Serine protease/helicase NS3
The N-terminal one-third of serine protease/helicase NS3 contains the protease activity (PubMed:11591719, PubMed:9261354). This region contains a zinc atom that does not belong to the active site, but may play a structural rather than a catalytic role (By similarity). This region is essential for the activity of protease NS2, maybe by contributing to the folding of the latter (By similarity). The NTPase/helicase activity is located in the twothirds C-terminus of NS3, this domain contains the NTPase and RNA-binding regions (PubMed:9614113).
Non-structural protein 4B
Contains a glycine zipper region that critically contributes to the biogenesis of functional ER-derived replication organelles.
Non-structural protein 5A
The N-terminus of NS5A acts as membrane anchor (By similarity). The central part of NS5A contains a variable region called interferon sensitivity determining region (ISDR) and seems to be intrinsically disordered and interacts with NS5B and host EIF2AK2 (Probable). The C-terminus of NS5A contains a variable region called variable region 3 (V3) (By similarity). ISDR and V3 may be involved in sensitivity and/or resistance to IFN-alpha therapy (By similarity). The C-terminus contains a nuclear localization signal (By similarity). The SH3-binding domain is involved in the interaction with host BIN1, GRB2 and Src-family kinases (By similarity).
Mature core protein
Packages viral RNA to form a viral nucleocapsid, and promotes virion budding (Probable). Participates in the viral particle production as a result of its interaction with the non-structural protein 5A (By similarity). Binds RNA and may function as a RNA chaperone to induce the RNA structural rearrangements taking place during virus replication (Probable). Modulates viral translation initiation by interacting with viral IRES and 40S ribosomal subunit (By similarity). Affects various cell signaling pathways, host immunity and lipid metabolism (Probable). Prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma signaling pathways and by blocking the formation of phosphorylated STAT1 and promoting ubiquitin-mediated proteasome-dependent degradation of STAT1 (By similarity). Activates STAT3 leading to cellular transformation (By similarity). Regulates the activity of cellular genes, including c-myc and c-fos (By similarity). May repress the promoter of p53, and sequester CREB3 and SP110 isoform 3/Sp110b in the cytoplasm (By similarity). Represses cell cycle negative regulating factor CDKN1A, thereby interrupting an important check point of normal cell cycle regulation (By similarity). Targets transcription factors involved in the regulation of inflammatory responses and in the immune response: suppresses NF-kappa-B activation, and activates AP-1 (By similarity). Binds to dendritic cells (DCs) via C1QR1, resulting in down-regulation of T-lymphocytes proliferation (By similarity). Alters lipid metabolism by interacting with hepatocellular proteins involved in lipid accumulation and storage (By similarity). Induces up-regulation of FAS promoter activity, and thereby contributes to the increased triglyceride accumulation in hepatocytes (steatosis) (By similarity).
Envelope glycoprotein E1
Forms a heterodimer with envelope glycoprotein E2, which mediates virus attachment to the host cell, virion internalization through clathrin-dependent endocytosis and fusion with host membrane (By similarity). Fusion with the host cell is most likely mediated by both E1 and E2, through conformational rearrangements of the heterodimer required for fusion rather than a classical class II fusion mechanism (By similarity). E1/E2 heterodimer binds host apolipoproteins such as APOB and APOE thereby forming a lipo-viro-particle (LVP) (By similarity). APOE associated to the LVP allows the initial virus attachment to cell surface receptors such as the heparan sulfate proteoglycans (HSPGs), syndecan-1 (SDC1), syndecan-1 (SDC2), the low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SCARB1) (By similarity). The cholesterol transfer activity of SCARB1 allows E2 exposure and binding of E2 to SCARB1 and the tetraspanin CD81 (By similarity). E1/E2 heterodimer binding on CD81 activates the epithelial growth factor receptor (EGFR) signaling pathway (By similarity). Diffusion of the complex E1-E2-EGFR-SCARB1-CD81 to the cell lateral membrane allows further interaction with Claudin 1 (CLDN1) and occludin (OCLN) to finally trigger HCV entry (By similarity).
Envelope glycoprotein E2
Forms a heterodimer with envelope glycoprotein E1, which mediates virus attachment to the host cell, virion internalization through clathrin-dependent endocytosis and fusion with host membrane (By similarity). Fusion with the host cell is most likely mediated by both E1 and E2, through conformational rearrangements of the heterodimer required for fusion rather than a classical class II fusion mechanism (By similarity). The interaction between envelope glycoprotein E2 and host apolipoprotein E/APOE allows the proper assembly, maturation and infectivity of the viral particles (By similarity). This interaction is probably promoted via the up-regulation of cellular autophagy by the virus (By similarity). E1/E2 heterodimer binds host apolipoproteins such as APOB and APOE thereby forming a lipo-viro-particle (LVP) (By similarity). APOE associated to the LVP allows the initial virus attachment to cell surface receptors such as the heparan sulfate proteoglycans (HSPGs), syndecan-1 (SDC1), syndecan-1 (SDC2), the low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SCARB1) (By similarity). The cholesterol transfer activity of SCARB1 allows E2 exposure and binding of E2 to SCARB1 and the tetraspanin CD81 (By similarity). E1/E2 heterodimer binding on CD81 activates the epithelial growth factor receptor (EGFR) signaling pathway (By similarity). Diffusion of the complex E1-E2-EGFR-SCARB1-CD81 to the cell lateral membrane allows further interaction with Claudin 1 (CLDN1) and occludin (OCLN) to finally trigger HCV entry (By similarity). Inhibits host EIF2AK2/PKR activation, preventing the establishment of an antiviral state (By similarity). Viral ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs), and on liver sinusoidal endothelial cells and macrophage-like cells of lymph node sinuses (By similarity). These interactions allow the capture of circulating HCV particles by these cells and subsequent facilitated transmission to permissive cells such as hepatocytes and lymphocyte subpopulations (By similarity). The interaction between E2 and host amino acid transporter complex formed by SLC3A2 and SLC7A5/LAT1 may facilitate viral entry into host cell (By similarity).
Viroporin p7
Ion channel protein that acts as a viroporin and plays an essential role in the assembly, envelopment and secretion of viral particles (By similarity). Regulates the host cell secretory pathway, which induces the intracellular retention of viral glycoproteins and favors assembly of viral particles (By similarity). Creates a pore in acidic organelles and releases Ca(2+) and H(+) in the cytoplasm of infected cells, leading to a productive viral infection (By similarity). High levels of cytoplasmic Ca(2+) may trigger membrane trafficking and transport of viral ER-associated proteins to viroplasms, sites of viral genome replication (Probable). This ionic imbalance induces the assembly of the inflammasome complex, which triggers the maturation of pro-IL-1beta into IL-1beta through the action of caspase-1 (By similarity). Targets also host mitochondria and induces mitochondrial depolarization (By similarity). In addition of its role as a viroporin, acts as a lipid raft adhesion factor (By similarity).
Protease NS2
Cysteine protease required for the proteolytic auto-cleavage between the non-structural proteins NS2 and NS3 (Probable) (PubMed:11591719). The N-terminus of NS3 is required for the function of NS2 protease (active region NS2-3) (PubMed:11591719). Promotes the initiation of viral particle assembly by mediating the interaction between structural and non-structural proteins (By similarity).
Serine protease/helicase NS3
Displays three enzymatic activities: serine protease with a chymotrypsin-like fold, NTPase and RNA helicase (PubMed:9614113). NS3 serine protease, in association with NS4A, is responsible for the cleavages of NS3-NS4A, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B (By similarity). The NS3/NS4A complex prevents phosphorylation of host IRF3, thus preventing the establishment of dsRNA induced antiviral state (By similarity). The NS3/NS4A complex induces host amino acid transporter component SLC3A2, thus contributing to HCV propagation (By similarity). NS3 RNA helicase binds to RNA and unwinds both dsDNA and dsRNA in the 3' to 5' direction, and likely resolves RNA complicated stable secondary structures in the template strand (By similarity). Binds a single ATP and catalyzes the unzipping of a single base pair of dsRNA (By similarity). Inhibits host antiviral proteins TBK1 and IRF3 thereby preventing the establishment of an antiviral state (By similarity). Cleaves host MAVS/CARDIF thereby preventing the establishment of an antiviral state (By similarity). Cleaves host TICAM1/TRIF, thereby disrupting TLR3 signaling and preventing the establishment of an antiviral state (By similarity).
Non-structural protein 4A
Peptide cofactor which forms a non-covalent complex with the N-terminal of NS3 serine protease (By similarity). The NS3/NS4A complex prevents phosphorylation of host IRF3, thus preventing the establishment of dsRNA induced antiviral state (By similarity). The NS3/NS4A complex induces host amino acid transporter component SLC3A2, thus contributing to HCV propagation (By similarity).
Non-structural protein 4B
Induces a specific membrane alteration that serves as a scaffold for the virus replication complex (By similarity). This membrane alteration gives rise to the so-called ER-derived membranous web that contains the replication complex (By similarity). NS4B self-interaction contributes to its function in membranous web formation (By similarity). Promotes host TRIF protein degradation in a CASP8-dependent manner thereby inhibiting host TLR3-mediated interferon signaling (By similarity). Disrupts the interaction between STING and TBK1 contributing to the inhibition of interferon signaling (By similarity).
Non-structural protein 5A
Phosphorylated protein that is indispensable for viral replication and assembly (By similarity). Both hypo- and hyperphosphorylated states are required for the viral life cycle (By similarity). The hyperphosphorylated form of NS5A is an inhibitor of viral replication (By similarity). Involved in RNA-binding and especially in binding to the viral genome (By similarity). Zinc is essential for RNA-binding (By similarity). Participates in the viral particle production as a result of its interaction with the viral mature core protein (By similarity). Its interaction with host VAPB may target the viral replication complex to vesicles. Down-regulates viral IRES translation initiation (By similarity). Mediates interferon resistance, presumably by interacting with and inhibiting host EIF2AK2/PKR (By similarity). Prevents BIN1-induced apoptosis (By similarity). Acts as a transcriptional activator of some host genes important for viral replication when localized in the nucleus (By similarity). Via the interaction with host PACSIN2, modulates lipid droplet formation in order to promote virion assembly (By similarity). Modulates TNFRSF21/DR6 signaling pathway for viral propagation (By similarity).
RNA-directed RNA polymerase
RNA-dependent RNA polymerase that performs primer-template recognition and RNA synthesis during viral replication. Initiates RNA transcription/replication at a flavin adenine dinucleotide (FAD), resulting in a 5'- FAD cap on viral RNAs. In this way, recognition of viral 5' RNA by host pattern recognition receptors can be bypassed, thereby evading activation of antiviral pathways.
Genome polyprotein
Specific enzymatic cleavages in vivo yield mature proteins (By similarity). The structural proteins, core, E1, E2 and p7 are produced by proteolytic processing by host signal peptidases (By similarity). The core protein precursor is synthesized as a 23 kDa, which is retained in the ER membrane through the hydrophobic signal peptide (PubMed:8862403). Cleavage by the signal peptidase releases the 21 kDa mature core protein (PubMed:8862403). The cleavage of the core protein precursor occurs between aminoacids 176 and 188 but the exact cleavage site is not known (PubMed:8862403). Some degraded forms of the core protein appear as well during the course of infection (PubMed:8862403). The other proteins (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B) are cleaved by the viral proteases (By similarity). Autoprocessing between NS2 and NS3 is mediated by the NS2 cysteine protease catalytic domain and regulated by the NS3 N-terminal domain (PubMed:11591719).
Mature core protein
Phosphorylated by host PKC and PKA.
Mature core protein
Ubiquitinated; mediated by UBE3A and leading to core protein subsequent proteasomal degradation.
Envelope glycoprotein E1
Highly N-glycosylated.
Envelope glycoprotein E2
Highly N-glycosylated.
Protease NS2
Palmitoylation is required for NS2/3 autoprocessing and E2 recruitment to membranes.
Non-structural protein 4B
Palmitoylated. This modification may play a role in its polymerization or in protein-protein interactions.
Non-structural protein 5A
Phosphorylated on serines in a basal form termed p56 (PubMed:11118372). p58 is a hyperphosphorylated form of p56 (By similarity). p56 and p58 coexist in the cell in roughly equivalent amounts (By similarity). Hyperphosphorylation is dependent on the presence of NS4A (By similarity). Host CSNK1A1/CKI-alpha or RPS6KB1 kinases may be responsible for NS5A phosphorylation (PubMed:15016873, PubMed:16943283).
Non-structural protein 5A
Tyrosine phosphorylation is essential for the interaction with host SRC.
RNA-directed RNA polymerase
The N-terminus is phosphorylated by host PRK2/PKN2.
Belongs to the hepacivirus polyprotein family.
Genome polyprotein
Proteins
327194Da
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