UniProtKB/Swiss-Prot entry P27958

• FUNCTION: Core protein packages viral RNA to form a viral nucleocapsid, and promotes virion budding. Modulates viral translation initiation by interacting with HCV IRES and 40S ribosomal subunit. Also regulates many host cellular functions such as signaling pathways and apoptosis. Prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma signaling pathways and by inducing human STAT1 degradation. Thought to play a role in virus-mediated cell transformation leading to hepatocellular carcinomas. Interacts with, and activates STAT3 leading to cellular transformation. May repress the promoter of p53, and sequester CREB3 and SP110 isoform 3/Sp110b in the cytoplasm. Also represses cell cycle negative regulating factor CDKN1A, thereby interrupting an important check point of normal cell cycle regulation. Targets transcription factors involved in the regulation of inflammatory responses and in the immune response: suppresses NK-kappaB activation, and activates AP-1. Could mediate apoptotic pathways through association with TNF-type receptors TNFRSF1A and LTBR, although its effect on death receptor-induced apoptosis remains controversial. Enhances TRAIL mediated apoptosis, suggesting that it might play a role in immune-mediated liver cell injury. Seric core protein is able to bind C1QR1 at the T-cell surface, resulting in down-regulation of T-lymphocytes proliferation. May transactivate human MYC, Rous sarcoma virus LTR, and SV40 promoters. May suppress the human FOS and HIV-1 LTR activity. Alters lipid metabolism by interacting with hepatocellular proteins involved in lipid accumulation and storage. Core protein induces up-regulation of FAS promoter activity, and thereby probably contributes to the increased triglyceride accumulation in hepatocytes (steatosis) (By similarity).
• FUNCTION: E1 and E2 glycoproteins form a heterodimer that is involved in virus attachment to the host cell, virion internalization through clathrin-dependent endocytosis and fusion with host membrane. E1/E2 heterodimer binds to human LDLR, CD81 and SCARB1/SR-BI receptors, but this binding is not sufficient for infection, some additional liver specific cofactors may be needed. The fusion function may possibly be carried by E1. E2 inhibits human EIF2AK2/PKR activation, preventing the establishment of an antiviral state. E2 is a 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. These interactions allow capture of circulating HCV particles by these cells and subsequent transmission to permissive cells. DCs act as sentinels in various tissues where they entrap pathogens and convey them to local lymphoid tissue or lymph node for establishment of immunity. 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).
• FUNCTION: P7 seems to be a heptameric ion channel protein (viroporin) and is inhibited by the antiviral drug amantadine (By similarity). Also inhibited by long-alkyl-chain iminosugar derivatives. Essential for infectivity.
• FUNCTION: Protease NS2-3 is a cysteine protease responsible for the autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation following maturation (By similarity).
• FUNCTION: NS3 displays three enzymatic activities: serine protease, NTPase and RNA helicase. NS3 serine protease, in association with NS4A, is responsible for the cleavages of NS3-NS4A, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B. NS3/NS4A complex also prevents phosphorylation of human IRF3, thus preventing the establishment of dsRNA induced antiviral state. NS3 RNA helicase binds to RNA and unwinds dsRNA in the 3' to 5' direction, and likely RNA stable secondary structure in the template strand (By similarity). Cleaves and inhibits the host antiviral protein MAVS.
• FUNCTION: NS4B induces a specific membrane alteration that serves as a scaffold for the virus replication complex. This membrane alteration gives rise to the so-called ER-derived membranous web that contains the replication complex. NS4B polymerization or in protein-protein interactions activity may contribute to its function in membranous web formation.
• FUNCTION: NS5A is a component of the replication complex involved in RNA-binding. Its interaction with Human VAPB may target the viral replication complex to vesicles. Down-regulates viral IRES translation initiation. Mediates interferon resistance, presumably by interacting with and inhibiting human EIF2AK2/PKR. Seems to inhibit apoptosis by interacting with BIN1 and FKBP8. The hyperphosphorylated form of NS5A is an inhibitor of viral replication (By similarity).
• FUNCTION: NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication.
• CATALYTIC ACTIVITY: 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'.
• CATALYTIC ACTIVITY: Nucleoside triphosphate + RNA(n) = diphosphate + RNA(n+1).
• CATALYTIC ACTIVITY: NTP + H₂O = NDP + phosphate.
• COFACTOR: Binds 1 zinc ion per NS3 protease domain (By similarity).
• COFACTOR: Binds 1 zinc ion per NS5A N-terminal domain (By similarity).
• ENZYME REGULATION: Activity of auto-protease NS2-3 is dependent on zinc ions and completely inhibited by EDTA. Serine protease NS3 is also activated by zinc ions (By similarity).
• SUBUNIT: Core protein is a homomultimer that binds the C-terminal part of E1 and interacts with numerous cellular proteins. Interaction with human STAT1 SH2 domain seems to result in decreased STAT1 phosphorylation, leading to decreased IFN-stimulated gene transcription. In addition to blocking the formation of phosphorylated STAT1, the core protein also promotes ubiquitin-mediated proteasome-dependent degradation of STAT1. Interacts with, and constitutively activates human STAT3. Associates with human LTBR and TNFRSF1A receptors and possibly induces apoptosis. Binds to human SP110 isoform 3/Sp110b, HNRPK, C1QR1, YWHAE, UBE3A/E6AP, DDX3X, APOA2 and RXRA proteins. Interacts with human CREB3 nuclear transcription protein, triggering cell transformation. May interact with human p53. Also binds human cytokeratins KRT8, KRT18, KRT19 and VIM (vimentin). E1 and E2 glycoproteins form a heterodimer that binds to human LDLR, CLDN1, CD81 and SCARB1 receptors. E2 binds and inhibits human EIF2AK2/PKR. Also binds human CD209/DC-SIGN and CLEC4M/DC-SIGNR. p7 forms a homoheptamer in vitro. NS2 forms a homodimer containing a pair of composite active sites at the dimerization interface. NS2 seems to interact with all other non-structural (NS) proteins. NS4A interacts with NS3 serine protease and stabilizes its folding. NS3-NS4A complex is essential for the activation of the latter and allows membrane anchorage of NS3. NS3 interacts with human TANK-binding kinase TBK1 and MAVS. NS4B and NS5A form homodimers and seem to interact with all other non-structural (NS) proteins. NS5A also interacts with human EIF2AK2/PKR, FKBP8, GRB2, BIN1, PIK3R1, SRCAP, VAPB and with most Src-family kinases. NS5B is a homooligomer and interacts with human VAPB (By similarity).
• INTERACTION:
  P06241:FYN (xeno); NbExp=4; IntAct=EBI-706378, EBI-515315;
  P62993:GRB2 (xeno); NbExp=3; IntAct=EBI-706378, EBI-401755;
  P08631:HCK (xeno); NbExp=5; IntAct=EBI-706378, EBI-346340;
  P06239:LCK (xeno); NbExp=1; IntAct=EBI-706378, EBI-1348;
  P06240:Lck (xeno); NbExp=3; IntAct=EBI-706378, EBI-1401;
  P07948:LYN (xeno); NbExp=5; IntAct=EBI-706378, EBI-79452;
  
• SUBCELLULAR LOCATION: Core protein p21: Endoplasmic reticulum membrane; Single-pass membrane protein (By similarity). Mitochondrion membrane; Single-pass type I membrane protein (By similarity). Lipid droplet membrane; Single-pass membrane protein (By similarity). Note=The C-terminal transmembrane domain of core protein p21 contains an ER signal leading the nascent polyprotein to the ER membrane. Only a minor proportion of core protein is present in the nucleus and an unknown proportion is secreted.
• SUBCELLULAR LOCATION: Core protein p19: Virion (By similarity). Cytoplasm (By similarity). Nucleus (By similarity). Secreted (By similarity).
• SUBCELLULAR LOCATION: Envelope glycoprotein E1: Endoplasmic reticulum membrane; Single-pass type I membrane protein. Note=The C-terminal transmembrane domain acts as a signal sequence and forms a hairpin structure before cleavage by host signal peptidase. After cleavage, the membrane sequence is retained at the C-terminus of the protein, serving as ER membrane anchor. A reorientation of the second hydrophobic stretch occurs after cleavage producing a single reoriented transmembrane domain. These events explain the final topology of the protein. ER retention of E1 is leaky and, in overexpression conditions, only a small fraction reaches the plasma membrane.
• SUBCELLULAR LOCATION: Envelope glycoprotein E2: Endoplasmic reticulum membrane; Single-pass type I membrane protein. Note=The C-terminal transmembrane domain acts as a signal sequence and forms a hairpin structure before cleavage by host signal peptidase. After cleavage, the membrane sequence is retained at the C-terminus of the protein, serving as ER membrane anchor. A reorientation of the second hydrophobic stretch occurs after cleavage producing a single reoriented transmembrane domain. These events explain the final topology of the protein. ER retention of E2 is leaky and, in overexpression conditions, only a small fraction reaches the plasma membrane.
• SUBCELLULAR LOCATION: p7: Endoplasmic reticulum membrane; Multi-pass membrane protein. Cell membrane. Note=The C-terminus of p7 membrane domain acts as a signal sequence. After cleavage by host signal peptidase, the membrane sequence is retained at the C-terminus of the protein, serving as ER membrane anchor. Only a fraction localizes to the plasma membrane.
• SUBCELLULAR LOCATION: Protease NS2-3: Endoplasmic reticulum membrane; Multi-pass membrane protein (Potential).
• SUBCELLULAR LOCATION: Serine protease/NTPase/helicase NS3: Endoplasmic reticulum membrane; Peripheral membrane protein (By similarity). Note=NS3 is associated to the ER membrane through its binding to NS4A.
• SUBCELLULAR LOCATION: Non-structural protein 4A: Endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential). Note=Membrane insertion occurs after processing by the NS3 protease.
• SUBCELLULAR LOCATION: Non-structural protein 4B: Endoplasmic reticulum membrane; Multi-pass membrane protein.
• SUBCELLULAR LOCATION: Non-structural protein 5A: Endoplasmic reticulum membrane; Peripheral membrane protein. Cytoplasm, perinuclear region. Mitochondrion. Note=Membrane insertion occurs after processing by the NS3 protease.
• SUBCELLULAR LOCATION: RNA-directed RNA polymerase: Endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential). Note=Membrane insertion occurs after processing by the NS3 protease.
• ALTERNATIVE PRODUCTS: 2 named isoforms [FASTA] produced by ribosomal frameshifting. The exact location of the ribosomal frameshift is unknown. The F protein seems to be generated by a -2 ribosomal frameshift located in the vicinity of codon 11 of the core protein coding sequence. However, some F proteins may also be generated by +1 ribosomal frameshift. Since the core gene encodes alternative reading frame proteins (ARFPs), many functions depicted for the core protein might belong to the ARFPs.

  Name Genome polyprotein Isoform ID P27958-1 Note: Produced by conventional translation. This is the isoform sequence displayed in this entry.

  Name F protein Synonyms Frameshifted protein Isoform ID P0C045-1 Note: Produced by ribosomal frameshifting. This isoform is stored in UniProtKB/Swiss-Prot entry P0C045.

• DOMAIN: The transmembrane regions of envelope E1 and E2 glycoproteins are involved in heterodimer formation, ER localization, and assembly of these proteins. Envelope E2 glycoprotein contain two highly variable regions called hypervariable region 1 and 2 (HVR1 and HVR2). E2 also contain two segments involved in CD81-binding. HVR1 is implicated in the SCARB1-mediated cell entry. HVR2 and CD81-binding regions may be involved in sensitivity and/or resistance to IFN-alpha therapy (By similarity).
• DOMAIN: The N-terminus of NS5A acts as membrane anchor. The central part of NS5A seems to be intrinsically disordered and interacts with NS5B and host PKR. The C-terminus of NS5A contains a variable region called variable region 3 (V3) (By similarity).
• DOMAIN: The SH3-binding domain of NS5A is involved in the interaction with human Bin1, GRB2 and Src-family kinases (By similarity).
• DOMAIN: The N-terminal one-third of serine protease NS3 contains the protease activity. This region contains a zinc atom that does not belong to the active site, but may play a structural rather than a catalytic role. This region is essential for the activity of protease NS2-3, maybe by contributing to the folding of the latter. The helicase activity is located in the C-terminus of NS3.
• PTM: Specific enzymatic cleavages in vivo yield mature proteins. The structural proteins, core, E1, E2 and p7 are produced by proteolytic processing by host signal peptidases. The core protein is synthesized as a 21 kDa precursor which is retained in the ER membrane through the hydrophobic signal peptide. Cleavage by the signal peptidase releases the 19 kDa mature core protein. The other proteins (p7, NS2-3, NS3, NS4A, NS4B, NS5A and NS5B) are cleaved by the viral proteases (By similarity).
• PTM: Envelope E1 and E2 glycoproteins are highly N-glycosylated.
• PTM: Core protein is phosphorylated by host PKC and PKA (By similarity).
• PTM: NS5A is phosphorylated in a basal form termed p56. p58 is an hyperphosphorylated form of p56. p56 and p58 coexist in the cell in roughly equivalent amounts. Hyperphosphorylation is dependent on the presence of NS4A. Human AKT1, RPS6KB1/p70S6K, MAP2K1/MEK1, MAP2K6/MKK6 and CSNK1A1/CKI-alpha kinases may be responsible for NS5A phosphorylation (By similarity).
• PTM: The N-terminus of a fraction of NS4B molecules seems to be relocated post-translationally from the cytoplasm to the ER lumen, with a 5th transmembrane segment. The C-terminus of NS2 may be lumenal with a fourth transmembrane segment (By similarity).
• PTM: Core protein is ubiquitinated; mediated by UBE3A and leading to core protein subsequent proteasomal degradation (By similarity).
• PTM: NS4B is palmitoylated. This modification may play a role in its polymerization or in protein-protein interactions.
• MISCELLANEOUS: Cell culture adaptation of the virus leads to mutations in NS5A, reducing its inhibitory effect on replication (By similarity).
• MISCELLANEOUS: Core protein exerts viral interference on hepatitis B virus when HCV and HBV coinfect the same cell, by suppressing HBV gene expression, RNA encapsidation and budding (By similarity).
• SIMILARITY: Belongs to the hepaciviruses polyprotein family.
• SIMILARITY: Contains 1 helicase ATP-binding domain.
• SIMILARITY: Contains 1 peptidase C18 domain [view classification].
• SIMILARITY: Contains 1 peptidase S29 domain [view classification].
• SIMILARITY: Contains 1 RdRp catalytic domain.
• CAUTION: The core gene probably also codes for alternative reading frame proteins (ARFPs). Many functions depicted for the core protein might belong to the ARFPs.
• WEB RESOURCE: Name=euHCVdb; Note=The European HCV database; URL="http://euhcvdb.ibcp.fr";.
• WEB RESOURCE: Name=HCV databases; URL="http://hcv.lanl.gov/content/hcv-db/";.