Roles and functions of SARS-CoV-2 proteins in host immune evasion

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evades the host immune system through a variety of regulatory mechanisms. The genome of SARS-CoV-2 encodes 16 non-structural proteins (NSPs), four structural proteins, and nine accessory proteins that play indispensable roles to suppress the production and signaling of type I and III interferons (IFNs). In this review, we discussed the functions and the underlying mechanisms of different proteins of SARS-CoV-2 that evade the host immune system by suppressing the IFN-β production and TANK-binding kinase 1 (TBK1)/interferon regulatory factor 3 (IRF3)/signal transducer and activator of transcription (STAT)1 and STAT2 phosphorylation. We also described different viral proteins inhibiting the nuclear translocation of IRF3, nuclear factor-κB (NF-κB), and STATs. To date, the following proteins of SARS-CoV-2 including NSP1, NSP6, NSP8, NSP12, NSP13, NSP14, NSP15, open reading frame (ORF)3a, ORF6, ORF8, ORF9b, ORF10, and Membrane (M) protein have been well studied. However, the detailed mechanisms of immune evasion by NSP5, ORF3b, ORF9c, and Nucleocapsid (N) proteins are not well elucidated. Additionally, we also elaborated the perspectives of SARS-CoV-2 proteins.

Keywords: SARS-CoV-2; accessory proteins; immune evasion; non-structural proteins; structural proteins.

Figure 1

Genome organization of SARS-CoV-2. The genome of SARS-CoV-2 consists of 16 non-structural proteins, ranging from NSP1 to NSP16, four structural proteins (S, E, M and N), and interspersed between these structural proteins are nine accessory proteins. (S, Spike protein; E, Envelop protein; M, Membrane protein; N, Nucleocapsid protein).

Figure 2

Innate immune system recognition, IFN signaling, and immune evasion by viruses. Upon sensing of viruses by RIG-I and MDA5, NF-κB, IRF3, and IRF7 stimulate the production of proinflammatory cytokines, IFN-I and IFN-III. IFNs are secreted in an autocrine and paracrine manner to induce the expression of ISGs via the JAK/STAT signaling pathway. (RIG-1, retinoic acid-inducible gene I; MDA5, melanoma differentiation-associated gene 5; NF-κB, nuclear factor-κB; IRF3, interferon regulatory factor 3; IRF7, interferon regulatory factor 7).

Figure 3

Host immune evasion by SARS-CoV-2 proteins. SARS-CoV-2 triggers IFN signaling pathway after being recognized by RIG-1 and MDA5. Different SARS-CoV-2 proteins interfere with these pathways in different ways. NSP8 and NSP13 inhibit TBK1 phosphorylation. NSP6, NSP8, NSP13, OR9b, and M inhibit IRF3 phosphorylation. NSP12, NSP14, NSP15, ORF6, and ORF9b inhibit the nuclear translocation of IRF3. NSP1, NSP6, NSP13, ORF3a, and ORF7b inhibit STAT1 phosphorylation. ORF9b inhibits TOM70. NSP6, NSP13, ORF7a, and ORF7b inhibit STAT2 phosphorylation. NSP13 and ORF6 inhibit the nuclear translocation of STAT1 to antagonize IFN signaling. ORF6 blocks STAT1 nuclear translocation by interacting with the Nup98-RAE1 complex and disrupts the interaction between Nup98 and importin-β1/importin-α1/PY-STAT1 complex, thus preventing the docking of this complex at the nuclear pore. ORF8 inhibits MHC-I to impair antigen-presenting cells. [NSP, non-structural protein; ORF, open reading frame; TOM70, translocase of outer membrane 70 KDa Subunit; IFN, interferon; STAT, signal transducer and activator of transcription; IRF3, interferon regulatory factor 3; IRF9, interferon regulatory factor 9; NF-κB, nuclear factor-κB; ISGs, interferon-stimulated genes; MHC-I, major histocompatibility complex I; Nup98-RAE1 complex, nucleoporin 98 (Nup98)–ribonucleic acid export 1 (RAE1)].