Inactive precursor of the viral replicase, which is activated by cleavages carried out by the viral protease nsP2. The early replication complex formed by the polyprotein P123 and nsP4 synthesizes the minus-strand RNAs (antigenome) (By similarity). 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 (By similarity). The early replication complex formed by the polyprotein P123' and nsP4 synthesizes minus-strand RNAs (antigenome) (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). Cytoplasmic capping enzyme that catalyzes two virus-specific reactions: methyltransferase and nsP1 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 (Probable). 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). Probably serves as a membrane anchor for the replication complex composed of nsP1-nsP4 (By similarity). Nsp1 is needed for the initiation of the minus-strand RNAs synthesis (By similarity). Palmitoylated nsP1 is remodeling host cell cytoskeleton, and induces filopodium-like structure formation at the surface of the host cell (By similarity). 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). Inhibits host translation to ensure maximal viral gene expression and evade host immune response (By similarity). 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 FXR 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-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 (By similarity). 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). 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). GTP + S-adenosyl-L-methionine = N(7)-methyl-GTP + S-adenosyl-L-homocysteine [nsP1 protein]-L-histidine + N(7)-methyl-GTP = [nsP1 protein]-N(tele)-(N(7)-methylguanosine 5'-phospho)-L-histidine + diphosphate [nsP1 protein]-N(tele)-(N(7)-methylguanosine 5'-phospho)-L-histidine + a 5'-end diphospho-(purine-ribonucleoside) in mRNA + H(+) = [nsP1 protein]-L-histidine + a 5'-end (N(7)-methyl 5'-triphosphoguanosine)-(purine-ribonucleoside) in mRNA a 5'-end triphospho-(purine-ribonucleoside) in mRNA + H2O = a 5'-end diphospho-(purine-ribonucleoside) in mRNA + H(+) + phosphate 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) 4-O-(ADP-D-ribosyl)-L-aspartyl-[protein] + H2O = ADP-D-ribose + H(+) + L-aspartyl-[protein] 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein] + H2O = ADP-D-ribose + H(+) + L-glutamyl-[protein] ATP + RNA(n) = diphosphate + RNA(n)-3'-adenine ribonucleotide ADP-beta-D-ribose 1''-phosphate + H2O = ADP-D-ribose + phosphate For nsP4 adenylyltransferase activity; Mn(2+) supports catalysis at 60% of the levels observed with Mg(2+). For nsP4 RNA-directed RNA polymerase activity. For nsP1 guanylylation. For nsP2 RNA triphosphatase activity. For nsP2 NTPase activity. Inhibited by sinefungin. Interacts with non-structural protein 3 (By similarity). Interacts with RNA-directed RNA polymerase nsP4 (By similarity). Interacts with protease nsP2 (By similarity). interacts with itself (By similarity). Interacts with mRNA-capping enzyme nsP1 (By similarity). Interacts with host DDX1 (By similarity). Interacts with host DDX3 (By similarity). Interacts (via C-terminus) with host FXR1; this interaction inhibits the formation of host stress granules on viral mRNAs and the nsp3-FXR1 complexes bind viral RNAs and probably orchestrate the assembly of viral replication complexes (By similarity). Interacts (via C-terminus) with host FXR2; this interaction inhibits the formation of host stress granules on viral mRNAs and the nsp3-FXR2 complexes bind viral RNAs and probably orchestrate the assembly of viral replication complexes (By similarity). Interacts (via C-terminus) with host FMR1; this interaction inhibits the formation of host stress granules on viral mRNAs and the nsp3-FMR1 complexes bind viral RNAs and probably orchestrate the assembly of viral replication complexes (By similarity). Interacts with mRNA-capping enzyme nsP1 (By similarity). Interacts with protease nsP2 (By similarity). interacts with itself (By similarity). Interacts with RNA-directed RNA polymerase nsP4 (By similarity). Interacts with mRNA-capping enzyme nsP1 (By similarity). Interacts with KPNA1/karyopherin-alpha1; this interaction probably allows the active transport of protease nsP2 into the host nucleus (By similarity). Part of cytoplasmic vesicles, which are probably formed at the plasma membrane and internalized leading to late endosomal/lysosomal spherules containing the replication complex. Part of cytoplasmic vesicles, which are probably formed at the plasma membrane and internalized leading to late endosomal/lysosomal spherules containing the replication complex. Part of cytoplasmic vesicles, which are probably formed at the plasma membrane and internalized leading to late endosomal/lysosomal spherules containing the replication complex. 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). 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). 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). 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 (Probable). 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. 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). 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 a region necessary and sufficient for formation of the nsP3/FXR complex (By similarity). 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 a region necessary and sufficient for formation of the nsP3'/FXR complex (By similarity). 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). 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). 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). Palmitoylated by host palmitoyltransferases ZDHHC2 and ZDHHC19. Phosphorylated by host on serines and threonines. Phosphorylated by host on serines and threonines. 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). Viral replication produces dsRNA in the late phase of infection, resulting in a strong activation of host EIF2AK2/PKR, leading to almost complete phosphorylation of EIF2A (By similarity). This inactivates completely cellular translation initiation, resulting shutoff of host proteins synthesis (By similarity). However, phosphorylation of EIF2A is probably not the only mechanism responsible for the host translation shutoff (By similarity). The viral translation can still occur normally because it relies on a hairpin structure in the coding region of sgRNA and is EIF2A-, EIF2D-, EIF4G- EIF4A-independent (By similarity). The genome codes for P123, but readthrough of a terminator codon UGA occurs between the codons for Gln-1885 and Arg-1887 giving rise to P1234. P1234 is cleaved quickly by nsP2 into P123' and nsP4 (By similarity). Further processing of p123' gives nsP1, nsP2 and nsP3' which is 6 amino acids longer than nsP3 since the cleavage site is after the readthrough (By similarity). This unusual molecular mechanism ensures that few nsP4 are produced compared to other non-structural proteins (By similarity). Mutant viruses with no alternative termination site grow significantly slower than wild-type virus (By similarity). The opal termination codon is frequently mutated to a sense codon on passage in cell culture (By similarity). The presence of the opal codon may be a requirement for viral maintenance in both vertebrate and invertebrate hosts and a selective advantage may be conferred in cell culture for the sense codon (By similarity).