Table 1 SARS-CoV-2 proteins responsible for innate immune interference

Nsp1

Blocks recognition by host sensors

Prevents phosphorylation of IRF3, possibly through translational shutoff that depletes the required cellular factors¹²¹

Blocks IFN signalling^a

Depletes TYK2 and STAT2 (ref. ¹²¹)

Blocks nuclear transport^a

Interacts with mRNA export receptor heterodimer NXF1–NXT1 and impairs its ability to interact with mRNA export factors and nucleoporins involved in nuclear export¹³⁷

Shuts off translation

Promotes degradation of cellular mRNA not containing 5′ viral leader sequence¹⁵⁵

Blocks the mRNA entry channel to the ribosome by binding via domains within its C terminus to the 18S structural RNA component of the 40S ribosomal subunit^{149,150,151,152,153}

Nsp3

Minimizes or masks inflammatory RNA

Required for formation of ER-associated DMVs⁶⁹

Blocks recognition by host sensors^a

PLpro domain deISGylates MDA5 (ref. ⁸⁸)

Cleaves IRF3 (refs. ^91,116)

Impairs host protein function^a

Macrodomain-X binds to and hydrolyses ADP-ribose bond with amino acid chains^92,93,94

PLpro domain deubiquitinates and deISGylates host signalling protein substrates^88,90,91

Nsp4

Minimizes or masks inflammatory RNA

Required for formation of ER-associated DMVs⁶⁹

Nsp5

Blocks recognition by host sensors^a

Inhibits the formation of stress granules⁸²

Cleaves N-terminal domain of RIG-I and prevents its interaction with MAVS⁹⁶

Promotes ubiquitination and degradation of MAVS⁹⁶

Cleaves IRF3 (refs. ^114,115,116)

Prevents nuclear translocation of IRF3; independent of Nsp5 protease activity or IRF3 phosphorylation¹¹⁴

Prevents phosphorylation and activation of NF-κB by cleaving TAB1 and NEMO^115,116,117

Nsp6

Minimizes or masks inflammatory RNA^a

Tethers DMVs to the ER⁶⁹

Blocks recognition by host sensors

Binds to and prevents phosphorylation-mediated activation of TBK1 (ref. ¹⁰⁵)

Blocks IFN signalling

Prevents phosphorylation of STAT1 and STAT2 (ref. ¹⁰⁵)

Nsp8

Shuts off translation

Binds to the 7SL RNA scaffold component of the SRP complex, blocking its ability to bind SRP54, which is necessary for signal peptide recognition¹⁴⁹

Nsp9

Blocks nuclear transport^a

Interacts with nuclear transport machinery and impairs expression of Nup62 on the nuclear envelope^136,138

Shuts off translation

Binds to the 7SL RNA scaffold component of the SRP complex, blocking its ability to bind SRP19, which is required for proper folding and assembly of SRP¹⁴⁹

Nsp10

Minimizes or masks inflammatory RNA

Acts as a cofactor for Nsp14 and Nsp16 during viral capping^58,59,60,61

Shuts off translation

Enhances Nsp14-mediated translational inhibition¹²⁴

Nsp12

Minimizes or masks inflammatory RNA^a

Acts as a guanylyltransferase during viral mRNA capping^52,57

Blocks recognition by host sensors

Prevents nuclear translocation of IRF3; independent of Nsp12 polymerase activity or IRF3 phosphorylation¹¹⁸

Nsp13

Minimizes or masks inflammatory RNA

5′ RNA triphosphatase activity during viral mRNA capping⁵⁷

Blocks recognition by host sensors

Binds to and prevents phosphorylation-mediated activation of TBK1^105,106

Blocks IFN signalling

Reduces endogenous levels of IFNAR1 (ref. ¹³¹)

Prevents phosphorylation of STAT1 and STAT2 (ref. ¹³²)

Nsp14

Minimizes or masks inflammatory RNA

N7-methyltransferase activity during viral mRNA capping⁵⁷

Blocks IFN signalling

Targets IFNAR1 for lysosomal degradation¹³¹

Activates NF-κB^a

Increases nuclear translocation of p65 and upregulation of pro-inflammatory chemokines, including IL-6 and IL-8 (ref. ¹⁹⁸)

Shuts off translation

Blocks protein synthesis in a manner dependent on ExoN domain and interaction with Nsp10 (ref. ¹²⁴)

Nsp15

Minimizes or masks inflammatory RNA

Endoribonuclease activity cleaves 5′-polyuridines from negative strand of viral RNAs to reduce accumulation of viral PAMPs⁶²

Blocks nuclear transport^a

Interacts with host nuclear transport machinery (nuclear transport factor 2)¹³⁶

Nsp16

Minimizes or masks inflammatory RNA

2′-O-methyltransferase activity during viral mRNA capping⁵⁸

Shuts off translation^a

Binds the mRNA recognition domains of snRNA U1 and U2 subunits of the spliceosome¹⁴⁹

ORF3a

Blocks IFN signalling

Prevents phosphorylation of STAT1 (ref. ¹⁰⁵)

ORF3b

Blocks recognition by host sensors

Prevents nuclear translocation of IRF3 (ref. ¹²⁰)

ORF6

Blocks nuclear transport^a

Binds karyopherin-α2 (KPNA2) importin¹⁰⁵

Binds to Nup98–Rae1 complex and prevents their association with the NPC^{136,139,140,141,142}

Promotes nuclear accumulation of host mRNAs and mRNA transporters; dependent on ORF6 C terminus^139,144

ORF7a

Blocks recognition by host sensors

Reduces expression of TBK1 (ref. ⁹⁷)

Blocks IFN signalling

Blocks phosphorylation of STAT1 and STAT2 (ref. ¹⁰⁵)

ORF7b

Blocks recognition by host sensors

Blocks RIG-I and MDA5 signalling in a MAVS-dependent manner^97,98

Blocks IFN signalling

Blocks phosphorylation of STAT1 and STAT2 (ref. ¹⁰⁵)

ORF8

Activates NF-κB^a

Viral mimic of IL-17A that induces heterodimerization of the human IL-17 receptor and downstream activation of NF-κB¹⁹⁹

ORF9b

Blocks recognition by host sensors

Prevents interaction between RIG-I and MAVS⁹⁷

Binds to TOM70 and inhibits the TOM70/HSP90 interaction, possibly leading to interference in TBK1/IRF3 signalling^109,110,111

Blocks TBK1 phosphorylation by preventing the interaction between TBK1 and TRIF¹⁰⁷

Spike (S)

Blocks recognition by host sensors

Potentiates proteasomal degradation of IRF3 (ref. ¹¹³)

Blocks IFN signalling

Prevents STAT1 from interacting with JAK1 (ref. ¹¹⁹)

Activates NF-κB

Promotes phosphorylation of p65 and IκBα; dependent on the S1 subunit²⁰⁰

Membrane (M)

Blocks recognition by host sensors

Blocks activation of MAVS by impairing its ability to form large aggregates necessary for recruitment of signalling adaptors⁹⁹

Reduces expression of TBK1 via ubiquitin-mediated degradation¹⁰⁴

Blocks nuclear transport

Binds KPNA6 importin and blocks its interaction with IRF3 (ref. ¹¹⁹)

Nucleocapsid

Minimizes/masks inflammatory RNA

Binds and destabilizes dsRNA⁷⁶

Inherent RNA-binding characteristics by virtue of its role in virion assembly^76,77,78

Blocks recognition by host sensors^a

Blocks formation of stress granules by binding and sequestering G3BP1 nucleating protein⁸²

Binds to DExD/H box RNA helicase domain of RIG-I and blocks its interaction with TRIM25 (refs. ^83,84,85)

Inhibits polyubiquitination and aggregation of MAVS, possibly via LLPS¹⁰⁰