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 (By similarity). 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 TNF-induced 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). 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). 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 transmission to permissive cells (By similarity). Capture of circulating HCV particles by these SIGN+ cells may facilitate virus infection of proximal hepatocytes and lymphocyte subpopulations and may be essential for the establishment of persistent infection (By similarity). Ion channel protein that acts as a viroporin and plays an essential role in the assembly, envelopment and secretion of viral particles (Probable). 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 (Probable). 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). Cysteine protease required for the proteolytic auto-cleavage between the non-structural proteins NS2 and NS3 (PubMed:17239391). The N-terminus of NS3 is required for the function of NS2 protease (active region NS2-3) (PubMed:17239391). Promotes the initiation of viral particle assembly by mediating the interaction between structural and non-structural proteins (By similarity). Displays three enzymatic activities: serine protease with a chymotrypsin-like fold, NTPase and RNA helicase (By similarity). 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). 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). 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 mature viral core protein (By similarity). Its interaction with host VAPB may target the viral replication complex to vesicles (By similarity). 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-dependent RNA polymerase that performs primer-template recognition and RNA synthesis during viral replication. Hydrolysis of four peptide bonds in the viral precursor polyprotein, commonly with Asp or Glu in the P6 position, Cys or Thr in P1 and Ser or Ala in P1'. a ribonucleoside 5'-triphosphate + H2O = a ribonucleoside 5'-diphosphate + H(+) + phosphate ATP + H2O = ADP + H(+) + phosphate a ribonucleoside 5'-triphosphate + RNA(n) = diphosphate + RNA(n+1) Activity of protease NS2 is dependent on zinc ions and completely inhibited by EDTA. This is probably due to the fact that NS2 protease activity needs NS3 N-terminus that binds a zinc atom (active region NS2-3). Binds 1 zinc ion, which has a structural role (PubMed:17239391). The magnesium ion is essential for the helicase activity (By similarity). Binds 2 magnesium ion that constitute a dinuclear catalytic metal center. Inhibited by the antiviral drug hexamethylene amiloride (By similarity). Inhibited by amantadine (PubMed:12560074). Inhibition by amantadine appears to be genotype-dependent (By similarity). Also inhibited by long-alkyl-chain iminosugar derivatives (By similarity). Activity is up-regulated by PRK2/PKN2-mediated phosphorylation. Homooligomer (By similarity). Interacts with E1 (via C-terminus) (By similarity). Interacts with the non-structural protein 5A (By similarity). Interacts (via N-terminus) with host STAT1 (via SH2 domain); this interaction results in decreased STAT1 phosphorylation and ubiquitin-mediated proteasome-dependent STAT1 degradation, leading to decreased IFN-stimulated gene transcription (By similarity). Interacts with host STAT3; this interaction constitutively activates STAT3 (By similarity). Interacts with host LTBR receptor (By similarity). Interacts with host TNFRSF1A receptor and possibly induces apoptosis (By similarity). Interacts with host HNRPK (By similarity). Interacts with host YWHAE (By similarity). Interacts with host UBE3A/E6AP (By similarity). Interacts with host DDX3X (By similarity). Interacts with host APOA2 (By similarity). Interacts with host RXRA protein (By similarity). Interacts with host SP110 isoform 3/Sp110b; this interaction sequesters the transcriptional corepressor SP110 away from the nucleus (By similarity). Interacts with host CREB3 nuclear transcription protein; this interaction triggers cell transformation (By similarity). Interacts with host ACY3 (By similarity). Interacts with host C1QR1 (By similarity). Interacts with host RBM24; this interaction, which enhances the interaction of the mature core protein with 5'-UTR, may inhibit viral translation and favor replication (By similarity). Interacts with host EIF2AK2/PKR; this interaction induces the autophosphorylation of EIF2AK2 (By similarity). Part of the viral assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By similarity). Forms a heterodimer with envelope glycoprotein E2 (By similarity). Interacts with mature core protein (By similarity). Interacts with protease NS2 (By similarity). The heterodimer E1/E2 interacts with host CLDN1; this interaction plays a role in viral entry into host cell (By similarity). Interacts with host SPSB2 (via C-terminus) (By similarity). Part of the viral assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By similarity). Forms a heterodimer with envelope glycoprotein E1 (By similarity). Interacts with host CD81 and SCARB1 receptors; these interactions play a role in viral entry into host cell (By similarity). Interacts with host EIF2AK2/PKR; this interaction inhibits EIF2AK2 and probably allows the virus to evade the innate immune response (By similarity). Interacts with host CD209/DC-SIGN and CLEC4M/DC-SIGNR (By similarity). Interact with host SPCS1; this interaction is essential for viral particle assembly (By similarity). Interacts with protease NS2 (By similarity). The heterodimer E1/E2 interacts with host CLDN1; this interaction plays a role in viral entry into host cell (By similarity). Part of the viral assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By similarity). Interacts with host SLC3A2/4F2hc; the interaction may facilitate viral entry into host cell (By similarity). Interacts with human PLSCR1 (By similarity). Homohexamer (PubMed:12560074). Homoheptamer (PubMed:17032656). Interacts with protease NS2 (By similarity). Homodimer (By similarity). Interacts with host SPCS1; this interaction is essential for viral particle assembly (By similarity). Interacts with envelope glycoprotein E1 (By similarity). Interacts with envelope glycoprotein E2 (By similarity). Interacts with viroporin p7 (By similarity). Interacts with serine protease/helicase NS3 (By similarity). Part of the replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA polymerase embedded in an ER-derived membranous web (By similarity). Part of the viral assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By similarity). Interacts with protease NS2 (By similarity). Interacts with non-structural protein 4A; this interaction stabilizes the folding of NS3 serine protease (By similarity). NS3-NS4A interaction is essential for NS3 activation and allows membrane anchorage of the latter (By similarity). NS3/NS4A complex also prevents phosphorylation of host IRF3, thus preventing the establishment of dsRNA induced antiviral state (By similarity). Interacts with host MAVS; this interaction leads to the cleavage and inhibition of host MAVS (By similarity). Interacts with host TICAM1; this interaction leads to the cleavage and inhibition of host TICAM1 (By similarity). Interacts with host TANK-binding kinase/TBK1; this interaction results in the inhibition of the association between TBK1 and IRF3, which leads to the inhibition of IRF3 activation (By similarity). Interacts with host RBM24 (By similarity). Part of the replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA polymerase embedded in an ER-derived membranous web (By similarity). Part of the viral assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By similarity). Interacts with NS3 serine protease; this interaction stabilizes the folding of NS3 serine protease (By similarity). NS3-NS4A interaction is essential for NS3 activation and allows membrane anchorage of the latter (By similarity). Interacts with non-structural protein 5A (via N-terminus) (By similarity). Part of the replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA polymerase embedded in an ER-derived membranous web (By similarity). Part of the viral assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By similarity). Homomultimer (By similarity). Interacts with non-structural protein NS5A (By similarity). Interacts with host PLA2G4C; this interaction likely initiates the recruitment of replication complexes to lipid droplets (By similarity). Interacts with host STING; this interaction disrupts the interaction between STING and TBK1 thereby suppressing the interferon signaling (By similarity). Part of the replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA polymerase embedded in an ER-derived membranous web (By similarity). Monomer (By similarity). Homodimer; dimerization is required for RNA-binding (By similarity). Interacts with mature core protein (By similarity). Interacts (via N-terminus) with non-structural protein 4A (By similarity). Interacts with non-structural protein 4B (By similarity). Interacts with RNA-directed RNA polymerase (By similarity). Part of the viral assembly initiation complex composed of NS2, E1, E2, NS3, NS4A, NS5A and the mature core protein (By similarity). Part of the replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA polymerase (By similarity). Interacts with host GRB2 (By similarity). Interacts with host BIN1 (By similarity). Interacts with host PIK3R1 (By similarity). Interacts with host SRCAP (By similarity). Interacts with host FKBP8 (By similarity). Interacts with host VAPB (By similarity). Interacts with host EIF2AK2/PKR; this interaction leads to disruption of EIF2AK2 dimerization by NS5A and probably allows the virus to evade the innate immune response (By similarity). Interacts (via N-terminus) with host PACSIN2 (via N-terminus); this interaction attenuates protein kinase C alpha-mediated phosphorylation of PACSIN2 by disrupting the interaction between PACSIN2 and PRKCA (By similarity). Interacts (via N-terminus) with host SRC kinase (via SH2 domain) (By similarity). Interacts with most Src-family kinases (By similarity). Interacts with host IFI27 and SKP2; promotes the ubiquitin-mediated proteasomal degradation of NS5A (By similarity). Interacts with host GPS2 (By similarity). Interacts with host TNFRSF21; this interaction allows the modulation by the virus of JNK, p38 MAPK, STAT3, and Akt signaling pathways in a DR6-dependent manner (By similarity). Interacts (via N-terminus) with host CIDEB (via N-terminus); this interaction seems to regulate the association of HCV particles with APOE (By similarity). Interacts with host CHKA/Choline Kinase-alpha; CHKA bridges host PI4KA and NS5A and potentiates NS5A-stimulated PI4KA activity, which then facilitates the targeting of the ternary complex to the ER for viral replication (By similarity). Interacts with host SPSB2 (via C-terminus); this interaction targets NS5A for ubiquitination and degradation (By similarity). Interacts with host RAB18; this interaction may promote the association of NS5A and other replicase components with lipid droplets (By similarity). Homooligomer (By similarity). Interacts with non-structural protein 5A (By similarity). Interacts with host VAPB (By similarity). Interacts with host PRK2/PKN2 (By similarity). Interacts with host HNRNPA1 and SEPT6; these interactions facilitate viral replication (By similarity). Part of the replication complex composed of NS2, NS3, NS4A, NS4B, NS5A and the RNA-directed RNA polymerase (By similarity). The C-terminal transmembrane domain of the core protein precursor contains an ER signal leading the nascent polyprotein to the ER membrane. Only a minor proportion of core protein is present in the nucleus (By similarity). Probably present on the surface of lipid droplets (By similarity). The C-terminal transmembrane domain acts as a signal sequence and forms a hairpin structure before cleavage by host signal peptidase (By similarity). After cleavage, the membrane sequence is retained at the C-terminus of the protein, serving as ER membrane anchor (By similarity). A reorientation of the second hydrophobic stretch occurs after cleavage producing a single reoriented transmembrane domain (By similarity). These events explain the final topology of the protein (By similarity). The C-terminal transmembrane domain acts as a signal sequence and forms a hairpin structure before cleavage by host signal peptidase (By similarity). After cleavage, the membrane sequence is retained at the C-terminus of the protein, serving as ER membrane anchor (By similarity). A reorientation of the second hydrophobic stretch occurs after cleavage producing a single reoriented transmembrane domain (By similarity). These events explain the final topology of the protein (By similarity). The C-terminus of p7 membrane domain acts as a signal sequence (By similarity). After cleavage by host signal peptidase, the membrane sequence is retained at the C-terminus of the protein, serving as ER membrane anchor (By similarity). ER retention of p7 is leaky and a small fraction reaches the plasma membrane (By similarity). Probably present on the surface of lipid droplets. NS3 is associated to the ER membrane through its binding to NS4A. Host membrane insertion occurs after processing by the NS3 protease. A reorientation of the N-terminus into the ER lumen occurs post-translationally. Host membrane insertion occurs after processing by the NS3 protease (By similarity). Localizes at the surface of lipid droplets (By similarity). Host membrane insertion occurs after processing by the NS3 protease. The transmembrane regions of envelope E1 and E2 glycoproteins are involved in heterodimer formation, ER localization, and assembly of these proteins. 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 (By similarity). HVR1 is implicated in the SCARB1-mediated cell entry and probably acts as a regulator of the association of particles with lipids (By similarity). The N-terminus of NS3 is required for the catalytic activity of protease NS2 (PubMed:17239391). The minimal catalytic region includes the C-terminus of NS2 and the N-terminus NS3 protease domain (active region NS2-3) (PubMed:17239391). The N-terminal one-third contains the protease activity (By similarity). This region contains a zinc atom that does not belong to the active site, but may play a structural rather than a catalytic role (PubMed:17239391). This region is essential for the activity of protease NS2, maybe by contributing to the folding of the latter (PubMed:17239391). The NTPase/helicase activity is located in the twothirds C-terminus of NS3, this domain contains the NTPase and RNA-binding regions (By similarity). Contains a glycine zipper region that critically contributes to the biogenesis of functional ER-derived replication organelles. 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 (By similarity). 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). 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 (By similarity). Cleavage by the signal peptidase releases the 21 kDa mature core protein (By similarity). The cleavage of the core protein precursor occurs between aminoacids 176 and 188 but the exact cleavage site is not known (By similarity). Some degraded forms of the core protein appear as well during the course of infection (By similarity). 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 (By similarity). Phosphorylated by host PKC and PKA. Ubiquitinated; mediated by UBE3A and leading to core protein subsequent proteasomal degradation. Highly N-glycosylated. Highly N-glycosylated. Palmitoylation is required for NS2/3 autoprocessing and E2 recruitment to membranes. Palmitoylated. This modification may play a role in its polymerization or in protein-protein interactions. Phosphorylated on serines in a basal form termed p56 (By similarity). 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 (By similarity). Tyrosine phosphorylation is essential for the interaction with host SRC. The N-terminus is phosphorylated by host PRK2/PKN2. Viral particle assembly takes place at the surface of ER-derived membranes in close proximity to lipid droplets. NS2 associates with E1/E2 glycoproteins, NS3 and NS5A, which interacts with the viral RNA and core protein to promote genome encapsidation. The nucleocapsid buds at the ER membrane where E1/E2 glycoproteins are anchored and afterward associate with nascent lipid droplet to acquire APOE and APOC. Secretion of viral particles is probably regulated by viroporin p7. Cell culture adaptation of the virus leads to mutations in NS5A, reducing its inhibitory effect on replication. Exerts viral interference on hepatitis B virus when HCV and HBV coinfect the same cell, by suppressing HBV gene expression, RNA encapsidation and budding. Belongs to the hepacivirus polyprotein family. The core gene probably also codes for alternative reading frame proteins (ARFPs). Many functions depicted for the core protein might belong to the ARFPs.