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Chikungunya virus nsP2

Domain

Protease nsP2

The N-terminus exhibits NTPase and RNA triphosphatase activities and is proposed to have helicase activity, whereas the C-terminus possesses protease activity (By similarity). Contains a nuclear localization signal and a nuclear export signal, these two motifs are probably involved in the shuttling between the cytoplasm and the nucleus of nsP2 (By similarity). The C-terminus is required for promoting the export of host STAT1 (By similarity).

mRNA-capping enzyme nsP1

The N-terminus binds a zinc ion which stabilizes this region (By similarity). The C-terminus is disordered (By similarity).

Non-structural protein 3

In the N-terminus, the macro domain displays a mono-ADP-ribosylhydrolase activity (By similarity). The central part called, the alphavirus unique domain (AUD) has a zinc-binding function (By similarity). The C-terminus region, also called hypervariable domain (HVD), is mainly disordered and binds several host proteins (By similarity). This intrinsically disordered domain contains 2 SH3 domain-binding sites and 2 FGDF motifs necessary and sufficient for the formation of nsP3/G3BP complexes (By similarity).

Non-structural protein 3'

In the N-terminus, the macro domain displays a mono-ADP-ribosylhydrolase activity (By similarity). The central part has a zinc-binding function (By similarity). The C-terminus contains two FGDF motifs necessary and sufficient for formation of the nsP3'/G3BP1 complex (By similarity).

Function

Polyprotein P1234

Inactive precursor of the viral replicase, which is activated by cleavages carried out by the viral protease nsP2.

Polyprotein P123

The early replication complex formed by the polyprotein P123 and nsP4 synthesizes minus-strand RNAs (By similarity). As soon P123 is cleaved into mature proteins, the plus-strand RNAs synthesis begins (By similarity).

Polyprotein P123'

The early replication complex formed by the polyprotein P123' and nsP4 synthesizes minus-strand RNAs (Probable). Polyprotein P123' is a short-lived polyprotein that accumulates during early stage of infection (Probable). As soon P123' is cleaved into mature proteins, the plus-strand RNAs synthesis begins (Probable).

mRNA-capping enzyme nsP1

Cytoplasmic capping enzyme that catalyzes two virus-specific reactions: methyltransferase and guanylyltransferase (By similarity). mRNA-capping is necessary since all viral RNAs are synthesized in the cytoplasm, and host capping enzymes are restricted to the nucleus (Probable). The enzymatic reaction involves a covalent link between 7-methyl-GMP and nsP1, whereas eukaryotic capping enzymes form a covalent complex only with GMP (By similarity). nsP1 capping consists in the following reactions: GTP is first methylated into 7-methyl-GMP and then is covalently linked to nsP1 to form the m7GMp-nsP1 complex from which 7-methyl-GMP complex is transferred to the mRNA to create the cap structure (By similarity). NsP1 is also needed for the initiation of the minus-strand RNAs synthesis (By similarity). At the initiation of virus replication, mediates the assembly of the viral replication complex made of the non-structural proteins, the association of this complex with the inner face of the plasma membrane and the formation of membranous spherules that serve as replication complex factories (By similarity). Forms the neck of these spherules with a central channel for mediating communication and the passage of RNA, nucleotides, and small proteins between the viral replication complex and the host cytoplasm (By similarity). Palmitoylated nsP1 is remodeling host cell cytoskeleton, and induces filopodium-like structure formation at the surface of the host cell (By similarity).

Protease nsP2

Multifunctional protein whose N-terminus is part of the RNA polymerase complex and displays NTPase, RNA triphosphatase and helicase activities (By similarity). NTPase and RNA triphosphatase are involved in viral RNA capping and helicase keeps a check on the dsRNA replication intermediates (By similarity). The C-terminus harbors a protease that specifically cleaves the polyproteins and releases the mature proteins (By similarity). Required for the shutoff of minus-strand RNAs synthesis (By similarity). Specifically inhibits the host IFN response by promoting the nuclear export of host STAT1 (By similarity). Also inhibits host transcription by inducing the rapid proteasome-dependent degradation of POLR2A, a catalytic subunit of the RNAPII complex (By similarity). The resulting inhibition of cellular protein synthesis serves to ensure maximal viral gene expression and to evade host immune response (By similarity).

Non-structural protein 3'

Seems to be essential for minus-strand RNAs and subgenomic 26S mRNAs synthesis (By similarity). Displays mono-ADP-ribosylhydrolase activity (Probable). ADP-ribosylation is a post-translational modification that controls various processes of the host cell and the virus probably needs to revert it for optimal viral replication (Probable). Binds proteins of FXR family and sequesters them into the viral RNA replication complexes thereby inhibiting the formation of host stress granules on viral mRNAs (Probable). The nsp3'-FXR complexes bind viral RNAs and probably orchestrate the assembly of viral replication complexes, thanks to the ability of FXR family members to self-assemble and bind DNA (Probable).

Non-structural protein 3

Seems to be essential for minus-strand RNAs and subgenomic 26S mRNAs synthesis (By similarity). Displays mono-ADP-ribosylhydrolase activity (By similarity). ADP-ribosylation is a post-translational modification that controls various processes of the host cell and the virus probably needs to revert it for optimal viral replication (By similarity). Binds proteins of G3BP family and sequesters them into the viral RNA replication complexes thereby inhibiting the formation of host stress granules on viral mRNAs (By similarity). The nsp3-G3BP complexes bind viral RNAs and probably orchestrate the assembly of viral replication complexes, thanks to the ability of G3BP family members to self-assemble and bind DNA (By similarity).

RNA-directed RNA polymerase nsP4

RNA dependent RNA polymerase (By similarity). Replicates genomic and antigenomic RNA by recognizing replications specific signals. The early replication complex formed by the polyprotein P123 and nsP4 synthesizes minus-strand RNAs (By similarity). The late replication complex composed of fully processed nsP1-nsP4 is responsible for the production of genomic and subgenomic plus-strand RNAs (By similarity).

Post-translational modifications

Polyprotein P1234

Specific enzymatic cleavages in vivo yield mature proteins (By similarity). The processing of the polyprotein is temporally regulated (By similarity). In early stages (1.7 hpi), P1234 is first cleaved in trans through its nsP2 protease activity, releasing P123' and nsP4, which associate to form the early replication complex (By similarity). At the same time, P1234 is also cut at the nsP1/nsP2 site early in infection but with lower efficiency (By similarity). After replication of the viral minus-strand RNAs (4 hpi), the polyproteins are cut at the nsP1/nsP2 and nsP2/nsP3 sites very efficiently, preventing accumulation of P123' and P1234 and allowing the formation of the late replication complex (By similarity). NsP3'/nsP4 site is not cleaved anymore and P34 is produced rather than nsP4 (By similarity).

Polyprotein P123

Specific enzymatic cleavages in vivo yield mature proteins (By similarity). The processing of the polyprotein is temporally regulated (By similarity). In early stages (1.7 hpi), P123 is cleaved at the nsP1/nsP2 site with low efficiency (By similarity). After replication of the viral minus-strand RNAs (4 hpi), the polyproteins are cut at the nsP1/nsP2 and nsP2/nsP3 sites very efficiently, preventing accumulation of P123 and allowing the formation of the late replication complex (By similarity).

Polyprotein P123'

Specific enzymatic cleavages in vivo yield mature proteins (By similarity). The processing of the polyprotein is temporally regulated (By similarity). In early stages (1.7 hpi), P123' is cleaved at the nsP1/nsP2 site with low efficiency (By similarity). After replication of the viral minus-strand RNAs (4 hpi), the polyproteins are cut at the nsP1/nsP2 and nsP2/nsP3 sites very efficiently, preventing accumulation of P123' and allowing the formation of the late replication complex (By similarity).

mRNA-capping enzyme nsP1

Palmitoylated by host palmitoyltransferases ZDHHC2 and ZDHHC19 (By similarity). Palmitoylation is increased by the interacton with host STING1 (By similarity).

Non-structural protein 3

Phosphorylated by host on serines and threonines.

Non-structural protein 3'

Phosphorylated by host on serines and threonines.

RNA-directed RNA polymerase nsP4

Ubiquitinated; targets the protein for rapid degradation via the ubiquitin system (By similarity). Nsp4 is present in extremely low quantities due to low frequency of translation through the amber stop-codon and the degradation by the ubiquitin pathway (By similarity).

Cellular localization

  • Polyprotein P1234
  • Host cytoplasmic vesicle membrane
  • Peripheral membrane protein
  • Part of cytoplasmic vesicles, which are probably formed at the plasma membrane and internalized leading to late endosomal/lysosomal spherules containing the replication complex.
  • Polyprotein P123'
  • Host cytoplasmic vesicle membrane
  • Peripheral membrane protein
  • Part of cytoplasmic vesicles, which are probably formed at the plasma membrane and internalized leading to late endosomal/lysosomal spherules containing the replication complex.
  • Polyprotein P123
  • Host cytoplasmic vesicle membrane
  • Peripheral membrane protein
  • Part of cytoplasmic vesicles, which are probably formed at the plasma membrane and internalized leading to late endosomal/lysosomal spherules containing the replication complex.
  • mRNA-capping enzyme nsP1
  • Host cytoplasmic vesicle membrane
  • Lipid-anchor
  • Host cell membrane
  • Lipid-anchor
  • Cytoplasmic side
  • Host cell projection
  • Host filopodium
  • In the late phase of infection, the polyprotein is quickly cleaved before localization to cellular membranes. Then a fraction of nsP1 localizes to the inner surface of the plasma membrane and its filopodial extensions. Only the palmitoylated nsP1 localizes to the host filopodia (By similarity). NsP1 is also part of cytoplasmic vesicles, which are probably formed at the plasma membrane and internalized leading to late endosomal/lysosomal spherules containing the replication complex (By similarity).
  • Protease nsP2
  • Host cytoplasmic vesicle membrane
  • Peripheral membrane protein
  • Host nucleus
  • Host cytoplasm
  • In the late phase of infection, the polyprotein is quickly cleaved before localization to cellular membranes. Then approximately half of nsP2 is found in the nucleus (By similarity). Shuttles between cytoplasm and nucleus (By similarity). NsP2 is also part of cytoplasmic vesicles, which are probably formed at the plasma membrane and internalized leading to late endosomal/lysosomal spherules containing the replication complex (By similarity).
  • Non-structural protein 3'
  • Host cytoplasmic vesicle membrane
  • Peripheral membrane protein
  • In the late phase of infection, the polyprotein is quickly cleaved before localization to cellular membranes. Then nsP3 and nsP3' form aggregates in cytoplasm (By similarity). NsP3' is also part of cytoplasmic vesicles, which are probably formed at the plasma membrane and internalized leading to late endosomal/lysosomal spherules containing the replication complex (By similarity).
  • Non-structural protein 3
  • Host cytoplasmic vesicle membrane
  • Peripheral membrane protein
  • In the late phase of infection, the polyprotein is quickly cleaved before localization to cellular membranes. Then nsP3 and nsP3' form aggregates in cytoplasm (By similarity). NsP3 is also part of cytoplasmic vesicles, which are probably formed at the plasma membrane and internalized leading to late endosomal/lysosomal spherules containing the replication complex (By similarity).
  • RNA-directed RNA polymerase nsP4
  • Host cytoplasmic vesicle membrane
  • Peripheral membrane protein
  • NsP4 is part of cytoplasmic vesicles, which are probably formed at the plasma membrane and internalized leading to late endosomal/lysosomal spherules containing the replication complex.

Alternative names

Polyprotein P1234, P1234, Non-structural polyprotein

Target type

Proteins

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