Gene Protein Function Impact on immune response action Comments Ref
Reduced CpG Decreased activity of ZAP and APOBEC3G ZAP expressed in immune cells (25)
ORF1a nsp1 Mediates RNA replication and processing. Involved in RNA degradation. Modulates calcineurin/ NFAT pathway. Cleaves host RNA. Inhibits cyclophilins and immunophilins. Blocks ATF2/c-Jun, IRF3 and IRF7, NFκB, decreases STAT1 phosphorylation. Interferes with RIG-1 pathway. Associated with immune pathogenicity and long-term cytokine dysregulation. Promotes host RNA degradation. (34–36)
nsp2 Replicase essential for proofreading replication. May bind to prohibitin 1 and 2, involved in apoptosis, mitochondrial biogenesis and intracellular signalling. Modulates host survival signalling. Associated with pathogenicity. Deletion attenuates viral growth and RNA synthesis. (37,38)
nsp3
Papain like protease (PLpro). Processes pp1a and pp1ab. Complexes with nsp4 and nsp6. Deubiquitinates and deISGylates host proteins Blocks IFNa, IFNβ, CXCL10 and CCL5. Inhibits TLR7 signalling by removing Lys63-linked polyubiquitination of TRAF3 and 6. Antagonizes IRF3, stabilizes IκBα thereby blocking NFκB signalling. Interacts with STING-TRAF-TBK1 complex.
Forms DMV and replication process evade innate immune recognition.
(33,39,40)
nsp4 Complexes with nsp3 and nsp6 to form the DMV. May anchor RTC to ER. Helps replication process evade innate immune recognition. (39)
nsp5
Chymotrypsin -like protease (3CLpro)
Induces apoptosis and growth arrest via caspase-3 and caspase-9.
(41)
nsp6 Complexes with nsp3 and nsp4 to form DMV. Helps replication process evade innate immune recognition. Activates autophagosome. (39)
nsp7 Complexes with nsp8 and nsp12 for viral replication Nsp7-nsp8 form the primase complex. (42)
nsp8 Complexes with nsp7 and nsp 12 for viral replication Nsp7-nsp8 form the primase complex. (42)
nsp9 Involved in viral genomic RNA reproduction but exact role unclear Interacts with nsp8 (43,44)
nsp10
Complexes with nsp 1,7 and 14. Multifunctional cofactor in replication.
Interacts with the oxido-reductase system causing cytopathic effect. Aids RNA capping thus evades RIG-1 and MDA5 recognition. Activator of nsp14 function. Forms a complex with nsp16. (26,45, 46)
nsp11 Peptide resulting from cleavage of pp1a at nsp10/11 junction Not known
ORF1b (nsps in addition to 1-11)
nsp12
RNA dependent RNA polymerase (RdRp)
Targeting mitochondria limits host cellular responses
(42)
nsp13 helicase key for efficient replication of viral genome Caps RNA thus evades RIG-I and MDA-5 signalling Failure to trigger IFIT1. (47)
nsp14
exon 3′–5′ exonuclease plays crucial role in viral RNA synthesis and capping. Complexes with nsp10.
Involved in the capping through its function as a guanine-N7 methyltransferase helping nsp16 evade RIG-1 and MDA5 recognition.
(48)
nsp15
uridylate -specific endoribonuclease (EndU)
Limits exposure of viral dsRNA to the sensors MDA5, PKR, and OAS/RNaseL. Inhibits poly U thereby evading MDA5 thus antagonizing IFN-a/β production.
(28)
nsp16 2’-O-ribose methyl transferase involved in RNA capping. Complexes with nsp10. Caps RNA thus evades RIG-I and MDA-5 signalling Failure to trigger IFIT1 (26,49)
ORF2
spike
Heavily glycosylated with 22 glycans. ACE/ACE-2 interaction. Requires priming to expose membrane fusion Masks immunogenic protein epitopes. Induced misbalanced in RAS that triggers inflammation. Masks immunogenic protein epitopes. (22,23, 50, 51)
ORF3a
ORF3a
Interact with SARS-CoV M, S, E, and 7a proteins Forms viroporins
Activates PERK pathway, triggers apoptosis through expression of ATF4 and CHOP. Downregulates and degrades Type 1 IFNR.
Expressed on cell surface. Induces fibrinogen, stress pathways, necrotic cell death, activates inflammasome.
(24,52–54)
ORF4 Envelope Essential for viral assembly and budding. Forms viroporins. Induces ROS and activates inflammasome (55,56)
ORF5 Membrane Important for viral assembly Inhibits type I interferon production by impeding the formation of TRAF3. TANK. TBK1/IKKepsilon complex Induces apoptosis. (57–59)
ORF6
ORF6
Plays a role in viral pathogenesis, interacts with ORF8. May aid viral virulence.
Inhibits STAT1 nuclear import
Promotes RNA polymerase activity
(53)
ORF7a
ORF7a
Interacts with S protein and p3a. Not essential for replication
Inhibits BST-2 glycosylation, leading to a loss of BST-2’s function. SARS-CoV ORF7a induces caspase-dependent apoptosis.
BST -2 restricts virion egress by tethering virions to plasma membrane. Interacts with LFA.
(60,61)
ORF7b ORF7b Not essential for viral replication but structural component of the virion. It is an integral membrane protein located in the Golgi compartment. (62)
ORF8 ORF8 Differs form other HCoVs Interact and downregulates MHC-I SARS-CoV encodes p8a and p8b that induce caspase-dependent apoptosis and activates UPR. (63)
ORF9
Nucleo-capsid
Stabilises viral RNA. Interacts with stress granules G3BP1.
Targets MAVS -TRAF3-TRAF6 and antagonizes IFN-β
(53,64, 65)
ORF10 ORF10 Ubiquitin ligase unknown