POLG_WNV

Domain

The transmembrane domains of the small envelope protein M and envelope protein E contain an endoplasmic reticulum retention signal.

Function

Capsid protein C

Plays a role in virus budding by binding to the cell membrane and gathering the viral RNA into a nucleocapsid that forms the core of a mature virus particle (By similarity). During virus entry, may induce genome penetration into the host cytoplasm after hemifusion induced by the surface proteins (By similarity). Can migrate to the cell nucleus where it modulates host functions (By similarity). Overcomes the anti-viral effects of host EXOC1 by sequestering and degrading the latter through the proteasome degradation pathway (PubMed:23522008).

Capsid protein C

Inhibits RNA silencing by interfering with host Dicer.

Peptide pr

Prevents premature fusion activity of envelope proteins in trans-Golgi by binding to envelope protein E at pH6.0. After virion release in extracellular space, gets dissociated from E dimers.

Protein prM

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. prM-E cleavage is inefficient, and many virions are only partially matured. These uncleaved prM would play a role in immune evasion.

Small envelope protein M

May play a role in virus budding. Exerts cytotoxic effects by activating a mitochondrial apoptotic pathway through M ectodomain. May display a viroporin activity.

Envelope protein E

Binds to host cell surface receptor and mediates fusion between viral and cellular membranes (PubMed:15367621). Envelope protein is synthesized in the endoplasmic reticulum in the form of heterodimer with protein prM (By similarity). They play a role in virion budding in the ER, and the newly formed immature particle is covered with 60 spikes composed of heterodimer between precursor prM and envelope protein E (By similarity). The virion is transported to the Golgi apparatus where the low pH causes dissociation of PrM-E heterodimers and formation of E homodimers (By similarity). prM-E cleavage is inefficient, and many virions are only partially matured (By similarity). These uncleaved prM would play a role in immune evasion (By similarity).

Non-structural protein 1

Involved in immune evasion, pathogenesis and viral replication. Once cleaved off the polyprotein, is targeted to three destinations: the viral replication cycle, the plasma membrane and the extracellular compartment. Essential for viral replication. Required for formation of the replication complex and recruitment of other non-structural proteins to the ER-derived membrane structures. Excreted as a hexameric lipoparticle that plays a role against host immune response. Antagonizing the complement function. Binds to the host macrophages and dendritic cells. Inhibits signal transduction originating from Toll-like receptor 3 (TLR3).

Non-structural protein 2A

Component of the viral RNA replication complex that functions in virion assembly and antagonizes the host alpha/beta interferon antiviral response.

Serine protease subunit NS2B

Required cofactor for the serine protease function of NS3. May have membrane-destabilizing activity and form viroporins (By similarity).

Serine protease NS3

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.

Non-structural protein 4A

Regulates the ATPase activity of the NS3 helicase activity. NS4A allows NS3 helicase to conserve energy during unwinding.

Peptide 2k

Functions as a signal peptide for NS4B and is required for the interferon antagonism activity of the latter.

Non-structural protein 4B

Induces the formation of ER-derived membrane vesicles where the viral replication takes place. Inhibits interferon (IFN)-induced host STAT1 phosphorylation and nuclear translocation, thereby preventing the establishment of cellular antiviral state by blocking the IFN-alpha/beta pathway. Inhibits STAT2 translocation in the nucleus after IFN-alpha treatment.

RNA-directed RNA polymerase NS5

Replicates the viral (+) and (-) RNA genome, and performs the capping of genomes in the cytoplasm (PubMed:17267492). NS5 methylates viral RNA cap at guanine N-7 and ribose 2'-O positions (PubMed:17267492). Besides its role in RNA genome replication, also prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) signaling pathway (By similarity). Inhibits host TYK2 and STAT2 phosphorylation, thereby preventing activation of JAK-STAT signaling pathway (By similarity).

Post-translational modifications

Genome polyprotein

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.

Protein prM

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.

Envelope protein E

Not N-glycosylated.

Non-structural protein 1

N-glycosylated. The excreted form is glycosylated and this is required for efficient secretion of the protein from infected cells.

RNA-directed RNA polymerase NS5

Phosphorylated on serines residues. This phosphorylation may trigger NS5 nuclear localization.

Sequence similarities

In the N-terminal section; belongs to the class I-like SAM-binding methyltransferase superfamily. mRNA cap 0-1 NS5-type methyltransferase family.

Cellular localization

• Capsid protein C
• Virion
• Host nucleus
• Host cytoplasm
• Host cytoplasm
• Host perinuclear region
• Peptide pr
• Secreted
• Small envelope protein M
• Virion membrane
• Multi-pass membrane protein
• Host endoplasmic reticulum membrane
• Multi-pass membrane protein
• ER membrane retention is mediated by the transmembrane domains.
• Envelope protein E
• Virion membrane
• Multi-pass membrane protein
• Host endoplasmic reticulum membrane
• Multi-pass membrane protein
• ER membrane retention is mediated by the transmembrane domains.
• Non-structural protein 1
• Secreted
• Host endoplasmic reticulum membrane
• Peripheral membrane protein
• Lumenal side
• Located in RE-derived vesicles hosting the replication complex.
• Non-structural protein 2A
• Host endoplasmic reticulum membrane
• Multi-pass membrane protein
• Serine protease subunit NS2B
• Host endoplasmic reticulum membrane
• Multi-pass membrane protein
• Serine protease NS3
• Host endoplasmic reticulum membrane
• Peripheral membrane protein
• Cytoplasmic side
• Remains non-covalently associated to serine protease subunit NS2B.
• Non-structural protein 4A
• Host endoplasmic reticulum membrane
• Multi-pass membrane protein
• Located in RE-associated vesicles hosting the replication complex.
• Non-structural protein 4B
• Host endoplasmic reticulum membrane
• Multi-pass membrane protein
• Located in RE-derived vesicles hosting the replication complex.
• RNA-directed RNA polymerase NS5
• Host endoplasmic reticulum membrane
• Peripheral membrane protein
• Cytoplasmic side
• Host nucleus
• Located in RE-associated vesicles hosting the replication complex. NS5 protein is mainly localized in the nucleus rather than in ER vesicles.

Alternative names

• Genome polyprotein

Database links

• swissprot:P06935

Target type

Proteins

Molecular weight

380110Da