Multifunctional protein involved in the transcription and replication of viral RNAs. Contains the proteinases responsible for the cleavages of the polyprotein. Inhibits host translation by associating with the open head conformation of the 40S subunit (PubMed:33479166, PubMed:33080218, PubMed:32680882, PubMed:32908316). The C-terminus binds to and obstructs ribosomal mRNA entry tunnel (PubMed:33479166, PubMed:33080218, PubMed:32680882, PubMed:32908316). Thereby inhibits antiviral response triggered by innate immunity or interferons (PubMed:33080218, PubMed:32680882, PubMed:32979938). The nsp1-40S ribosome complex further induces an endonucleolytic cleavage near the 5'UTR of host mRNAs, targeting them for degradation (By similarity). Viral mRNAs less susceptible to nsp1-mediated inhibition of translation, because of their 5'-end leader sequence (PubMed:32908316, PubMed:33080218). May play a role in the modulation of host cell survival signaling pathway by interacting with host PHB and PHB2. Indeed, these two proteins play a role in maintaining the functional integrity of the mitochondria and protecting cells from various stresses. Responsible for the cleavages located at the N-terminus of the replicase polyprotein. Participates together with nsp4 in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication (By similarity). Forms a molecular pore spanning the double membrane of the coronavirus replication organelle (PubMed:32763915). Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF3 (PubMed:32733001). Prevents also host NF-kappa-B signaling (By similarity). In addition, PL-PRO possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates (PubMed:32726803). Cleaves preferentially ISG15 from antiviral protein IFIH1 (MDA5), but not DDX58 (RIG-I) (PubMed:33727702). Can play a role in host ADP-ribosylation by binding ADP-ribose (PubMed:32578982). Participates in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication. Cleaves the C-terminus of replicase polyprotein at 11 sites (PubMed:32321856). Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SGACN] (PubMed:32198291, PubMed:32272481). Also able to bind an ADP-ribose-1''-phosphate (ADRP) (By similarity) (PubMed:32198291, PubMed:32272481). Plays a role in the initial induction of autophagosomes from host reticulum endoplasmic (By similarity). Later, limits the expansion of these phagosomes that are no longer able to deliver viral components to lysosomes (By similarity). Binds to host TBK1 without affecting TBK1 phosphorylation; the interaction with TBK1 decreases IRF3 phosphorylation, which leads to reduced IFN-beta production (PubMed:32979938). Plays a role in viral RNA synthesis (PubMed:32358203, PubMed:32277040, PubMed:32438371, PubMed:32526208). Forms a hexadecamer with nsp8 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers (By similarity). Plays a role in viral RNA synthesis (PubMed:32358203, PubMed:32277040, PubMed:32438371, PubMed:32526208). Forms a hexadecamer with nsp7 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers (By similarity). Interacts with ribosome signal recognition particle RNA (SRP) (PubMed:33080218). Together with NSP9, suppress protein integration into the cell membrane, thereby disrupting host immune defenses (PubMed:33080218). May participate in viral replication by acting as a ssRNA-binding protein (By similarity). Interacts with ribosome signal recognition particle RNA (SRP) (PubMed:33080218). Together with NSP9, suppress protein integration into the cell membrane, thereby disrupting host immune defenses (PubMed:33080218). Plays a pivotal role in viral transcription by stimulating both nsp14 3'-5' exoribonuclease and nsp16 2'-O-methyltransferase activities. Therefore plays an essential role in viral mRNAs cap methylation. Responsible for replication and transcription of the viral RNA genome. Multi-functional protein with a zinc-binding domain in N-terminus displaying RNA and DNA duplex-unwinding activities with 5' to 3' polarity. Activity of helicase is dependent on magnesium (By similarity). Binds to host TBK1 and inhibits TBK1 phosphorylation; the interaction with TBK1 decreases IRF3 phosphorylation, which leads to reduced IFN-beta production (PubMed:32979938). Enzyme possessing two different activities: an exoribonuclease activity acting on both ssRNA and dsRNA in a 3' to 5' direction and a N7-guanine methyltransferase activity. Acts as a proofreading exoribonuclease for RNA replication, thereby lowering The sensitivity of the virus to RNA mutagens. Plays a role in viral transcription/replication and prevents the simultaneous activation of host cell dsRNA sensors, such as MDA5/IFIH1, OAS, and PKR (By similarity). Acts by degrading the 5'-polyuridines generated during replication of the poly(A) region of viral genomic and subgenomic RNAs (PubMed:33504779, PubMed:33564093). Catalyzes a two-step reaction in which a 2'3'-cyclic phosphate (2'3'-cP) is first generated by 2'-O transesterification, which is then hydrolyzed to a 3'-phosphate (3'-P) (PubMed:33504779, PubMed:33564093). If not degraded, poly(U) RNA would hybridize with poly(A) RNA tails and activate host dsRNA sensors (By similarity). Methyltransferase that mediates mRNA cap 2'-O-ribose methylation to the 5'-cap structure of viral mRNAs (By similarity). N7-methyl guanosine cap is a prerequisite for binding of nsp16. Therefore plays an essential role in viral mRNAs cap methylation which is essential to evade immune system (By similarity). May disrupt host mRNA splicing in nucleus by interacting with pre-mRNA Recognition Domains ofthe U1 and U2 snRNAs (PubMed:33080218). a ribonucleoside 5'-triphosphate + RNA(n) = diphosphate + RNA(n+1) ATP + H2O = ADP + H(+) + phosphate ATP + H2O = ADP + H(+) + phosphate TSAVLQ-|-SGFRK-NH2 and SGVTFQ-|-GKFKK the two peptides corresponding to the two self-cleavage sites of the SARS 3C-like proteinase are the two most reactive peptide substrates. The enzyme exhibits a strong preference for substrates containing Gln at P1 position and Leu at P2 position. Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal). a 5'-end (N(7)-methyl 5'-triphosphoguanosine)-ribonucleoside in mRNA + S-adenosyl-L-methionine = a 5'-end (N(7)-methyl 5'-triphosphoguanosine)-(2'-O-methyl-ribonucleoside) in mRNA + H(+) + S-adenosyl-L-homocysteine uridylyl-uridylyl-ribonucleotide-RNA = a 3'-end uridylyl-2',3'-cyclophospho-uridine-RNA + a 5'-end dephospho-ribonucleoside-RNA Likely affects Nsp15 binding to RNA. Inhibited in vitro by GRL-0617. Inhibited by Remdesivir antiviral drug (GS-5734). Inhibited by Remdesivir antiviral drug (GS-5734) through non-obligate RNA chain termination. Inhibited by pyridone-containing alpha-ketoamides compounds 13a and 13b. In turn, alpha-ketoamide 13b (tert-butyl (1-((S)-1-(((S)-4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate) inhibits SARS-CoV-2 replication in human lung cells (PubMed:32198291). Inhibited ex vivo by michael acceptor inhibitor N3 (PubMed:32272481). Inhibited ex vivo by compound 11a and 11b (PubMed:32321856). Interacts with host PHB and PHB2. May for homohexamers. 3CL-PRO exists as monomer and homodimer. Only the homodimer shows catalytic activity. Interacts with PL-PRO and nsp6. Interacts with host TBK1; this interaction decreases by 57% IRF3 phosphorylation, which leads to reduced IFN-beta production. Eight copies of nsp7 and eight copies of nsp8 assemble to form a heterohexadecamer dsRNA-encircling ring structure (By similarity). Interacts with RNA-directed RNA polymerase (PubMed:32277040, PubMed:32358203, PubMed:32438371, PubMed:32526208). Eight copies of nsp7 and eight copies of nsp8 assemble to form a heterohexadecamer dsRNA-encircling ring structure (By similarity). Interacts with RNA-directed RNA polymerase (PubMed:32277040, PubMed:32358203, PubMed:32438371, PubMed:32526208). Is a dimer. Forms a dodecamer and interacts with nsp14 and nsp16; these interactions enhance nsp14 and nsp16 enzymatic activities. Interacts with nsp7 and nsp8. Interacts with host TBK1; this interaction inhibits TBK1 phosphorylation and decreases by 75% IRF3 phosphorylation, which leads to reduced IFN-beta production. Interacts (via N-terminus) with DDX1. Interacts with nsp10. Homohexamer. Interacts with nsp10. Localizes in virally-induced cytoplasmic double-membrane vesicles. nsp7, nsp8, nsp9 and nsp10 are localized in cytoplasmic foci, largely perinuclear. Late in infection, they merge into confluent complexes. nsp7, nsp8, nsp9 and nsp10 are localized in cytoplasmic foci, largely perinuclear. Late in infection, they merge into confluent complexes. nsp7, nsp8, nsp9 and nsp10 are localized in cytoplasmic foci, largely perinuclear. Late in infection, they merge into confluent complexes. nsp7, nsp8, nsp9 and nsp10 are localized in cytoplasmic foci, largely perinuclear. Late in infection, they merge into confluent complexes. The helicase interacts with the N protein in membranous complexes and colocalizes with sites of synthesis of new viral RNA. Normal translation results in Replicase polyprotein 1a. Ribosomal frameshifting at the end of this protein occurs at low frequency and produces Replicase polyprotein 1ab. The hydrophobic domains (HD) could mediate the membrane association of the replication complex and thereby alter the architecture of the host cell membrane. Specific enzymatic cleavages in vivo by its own proteases yield mature proteins. 3CL-PRO and PL-PRO proteinases are autocatalytically processed. Variant B.1.1.7 is also called Variant Of Concern (VOC) 202012/01, Variant Under Investigation (VUI) 202012/01, or 20B/501Y.V1. Variant Omicron/BA.1 and BA.2 belong to a lineage first isolated in South Africa (November 2021). Produced by -1 ribosomal frameshifting at the 1a-1b genes boundary. Belongs to the coronaviruses polyprotein 1ab family.