Binds to host cell surface receptors and mediates fusion between viral and cellular membranes. Efficient virus attachment to cell is, at least in part, mediated by host HAVCR1 in a cell-type specific manner (By similarity). In addition, host NCAM1 can also be used as entry receptor (By similarity). Interaction with host HSPA5 plays an important role in the early stages of infection as well (By similarity). Envelope protein is synthesized in the endoplasmic reticulum and forms a heterodimer with protein prM. The heterodimer plays a role in virion budding in the ER, and the newly formed immature particle is covered with 60 spikes composed of heterodimers between precursor prM and envelope protein E. The virion is transported to the Golgi apparatus where the low pH causes the dissociation of PrM-E heterodimers and formation of E homodimers. PrM-E cleavage is inefficient, many virions are only partially matured and immature prM-E proteins could play a role in immune evasion (By similarity).
Cleaved in post-Golgi vesicles by a host furin, releasing the mature small envelope protein M, and peptide pr. This cleavage is incomplete as up to 30% of viral particles still carry uncleaved prM.
Component of the viral RNA replication complex that recruits genomic RNA, the structural protein prM/E complex, and the NS2B/NS3 protease complex to the virion assembly site and orchestrates virus morphogenesis (By similarity). Antagonizes also the host MDA5-mediated induction of alpha/beta interferon antiviral response (PubMed:31882898, PubMed:31581385). May disrupt adherens junction formation and thereby impair proliferation of radial cells in the host cortex (PubMed:28826723).
Comprises a methyltransferase (MTase) in the N-terminal region and an RNA-dependent RNA polymerase in the C-terminal region.
Displays three enzymatic activities: serine protease, NTPase and RNA helicase. NS3 serine protease, in association with NS2B, performs its autocleavage and cleaves the polyprotein at dibasic sites in the cytoplasm: C-prM, NS2A-NS2B, NS2B-NS3, NS3-NS4A, NS4A-2K and NS4B-NS5. NS3 RNA helicase binds RNA and unwinds dsRNA in the 3' to 5' direction. Leads to translation arrest when expressed ex vivo (By similarity).
Forms a heterodimer with NS2B (By similarity). Interacts with NS4B (By similarity). Interacts with unphosphorylated RNA-directed RNA polymerase NS5; this interaction stimulates RNA-directed RNA polymerase NS5 guanylyltransferase activity (By similarity). Interacts with non-structural protein 2A (By similarity). Interacts with host SHFL; this interaction promotes NS3 degradation via a lysosome-dependent pathway (PubMed:32150556).
Forms a heterodimer with serine protease NS3 (By similarity). May form homooligomers (By similarity). Interacts with human SPCS1 (PubMed:29593046). Interacts with non-structural protein 2A (By similarity).
Forms heterodimers with envelope protein E in the endoplasmic reticulum and Golgi (By similarity). Interacts with non-structural protein 2A (By similarity).
Functions as a signal peptide for NS4B and is required for the interferon antagonism activity of the latter.
Homodimer (PubMed:28876240, PubMed:31090058). Interacts with host STAT2; this interaction inhibits the phosphorylation of the latter, and, when all viral proteins are present (polyprotein), targets STAT2 for degradation (PubMed:27212660, PubMed:27797853). Interacts with host TBK1 and IKBKE; these interactions lead to the inhibition of the host RIG-I signaling pathway (PubMed:30530224, PubMed:31690057). Interacts with host KPNA2 (PubMed:30848123). Interacts with host PAF1 complex; the interaction may prevent the recruitment of the host PAF1 complex to interferon-responsive genes, and thus reduces the immune response (By similarity). Interacts with serine protease NS3 (By similarity). Interacts with host KPNA2 (PubMed:30848123).
Homodimer; Homohexamer when secreted (PubMed:27455458). Interacts with host TBK1 (PubMed:28373913). Interacts with host USP8 (PubMed:30065070). Interacts with envelope protein E (By similarity).
Homodimer; in the endoplasmic reticulum and Golgi (By similarity). Interacts with host TYRO3, AXL and DC-SIGN proteins (By similarity). Interacts with non-structural protein 2A (By similarity). Interacts with host HAVCR1; this interaction likely mediates virus attachment to host cell (By similarity). Interacts with host NCAM1 (By similarity). Interacts with host HSPA5 (By similarity).
In the N-terminal section; belongs to the class I-like SAM-binding methyltransferase superfamily. mRNA cap 0-1 NS5-type methyltransferase family.
Induces the formation of ER-derived membrane vesicles where the viral replication takes place (By similarity). Also plays a role in the inhibition of host RLR-induced interferon-beta production at TANK-binding kinase 1/TBK1 level (PubMed:28373913). Cooperatively with NS4A suppresses the Akt-mTOR pathway and leads to cellular dysregulation (PubMed:27524440).
Inhibits RNA silencing by interfering with host Dicer.
Interacts with serine protease NS3. Interacts with NS1 (By similarity). Interacts with host TBK1.
Interacts with the structural protein prM/E complex, and the NS2B/NS3 protease complex.
May interact with host ANKLE2; the interaction may cause defects in brain development, such as microcephaly (PubMed:30550790). May interact with host SRPRA and SEC61G (PubMed:30550790).
May play a role in virus budding. Exerts cytotoxic effects by activating a mitochondrial apoptotic pathway through M ectodomain. May display a viroporin activity.
N-glycosylated. The excreted form is glycosylated, which is required for efficient secretion of the protein from infected cells.
N-glycosylation plays a role in virulence in mammalian and mosquito hosts, but may have no effect on neurovirulence.
Phosphorylated on serines residues. This phosphorylation may trigger NS5 nuclear localization.
Plays a role in host immune defense modulation and protection of envelope protein E during virion synthesis. PrM-E cleavage is inefficient, many virions are only partially matured and immature prM-E proteins could play a role in immune evasion. Contributes to fetal microcephaly in humans. Acts as a chaperone for envelope protein E during intracellular virion assembly by masking and inactivating envelope protein E fusion peptide. prM is the only viral peptide matured by host furin in the trans-Golgi network probably to avoid catastrophic activation of the viral fusion activity in acidic Golgi compartment prior to virion release.
Plays a role in the inhibition of host RLR-induced interferon-beta activation by targeting TANK-binding kinase 1/TBK1 (PubMed:28373913). In addition, recruits the host deubiquitinase USP8 to cleave 'Lys-11'-linked polyubiquitin chains from caspase-1/CASP1 thus inhibiting its proteasomal degradation. In turn, stabilized CASP1 promotes cleavage of cGAS, which inhibits its ability to recognize mitochondrial DNA release and initiate type I interferon signaling (PubMed:28373913).
Plays a role in virus budding by binding to the host cell membrane and packages the viral RNA into a nucleocapsid that forms the core of the mature virus particle. During virus entry, may induce genome penetration into the host cytoplasm after hemifusion induced by the surface proteins. Can migrate to the cell nucleus where it modulates host functions.
Prevents premature fusion activity of envelope proteins in trans-Golgi by binding to envelope protein E at pH 6.0. After virion release in extracellular space, gets dissociated from E dimers.
Regulates the ATPase activity of the NS3 helicase activity (By similarity). NS4A allows NS3 helicase to conserve energy during unwinding (By similarity). Cooperatively with NS4B suppresses the Akt-mTOR pathway and leads to cellular dysregulation (PubMed:27524440). By inhibiting host ANKLE2 functions, may cause defects in brain development, such as microcephaly (PubMed:30550790). Antagonizes also the host MDA5-mediated induction of alpha/beta interferon antiviral response (PubMed:31581385). Leads to translation arrest when expressed ex vivo (By similarity).
Replicates the viral (+) and (-) RNA genome, and performs the capping of genomes in the cytoplasm (PubMed:31090058). Methylates viral RNA cap at guanine N-7 and ribose 2'-O positions. Once sufficient NS5 is expressed, binds to the cap-proximal structure and inhibits further translation of the viral genome (PubMed:32313955). Besides its role in RNA genome replication, also prevents the establishment of a cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) signaling pathway. Mechanistically, interferes with host kinases TBK1 and IKKE upstream of interferon regulatory factor 3/IRF3 to inhibit the RIG-I pathway (PubMed:31690057, PubMed:30530224). Antagonizes also type I interferon signaling by targeting STAT2 for degradation by the proteasome thereby preventing activation of JAK-STAT signaling pathway (PubMed:27212660, PubMed:27797853). Within the host nucleus, disrupts host SUMO1 and STAT2 co-localization with PML, resulting in PML degradation (By similarity). May also reduce immune responses by preventing the recruitment of the host PAF1 complex to interferon-responsive genes (By similarity).
Required cofactor for the serine protease function of NS3.
Specific enzymatic cleavages in vivo yield mature proteins. Cleavages in the lumen of endoplasmic reticulum are performed by host signal peptidase, whereas cleavages in the cytoplasmic side are performed by serine protease NS3. Signal cleavage at the 2K-4B site requires a prior NS3 protease-mediated cleavage at the 4A-2K site.
Sumoylated, required for regulating IFN induced interferon stimulated genes/ISGs.
The central disordered region transitions to ordered by binding to NS3.
The disordered region at the N-terminus may be involved in lipid-droplet binding.
The strain Mr 766 lacks four amino-acids compared to circulating strains, removing the glycosylation site. This may be due to many cell culture passages since its isolation.
The transmembrane domain contains an endoplasmic reticulum retention signal.
Ubiquitination by host TRIM7 promotes virus attachment and fusion of the virus and the host endosome membrane.