Interaction of HDAC2 with SARS-CoV-2 NSP5 and IRF3 Is Not Required for NSP5-Mediated Inhibition of Type I Interferon Signaling Pathway

Abstract

SARS-CoV-2 has developed multiple strategies to antagonize the host antiviral response, such as blocking the IFN signaling pathway, which favors the replication and spreading of the virus. A recent SARS-CoV-2 protein interaction mapping revealed that the main viral protease NSP5 interacts with the host epigenetic factor HDAC2, but the interaction was not confirmed experimentally and its biological importance remains unclear.

SARS-COV-2 NSP5 Antagonizes MHC II Expresion by Subverting Histone Deacetylase 2

“…This is consistent with the work of Naik et al . who observed a similar non-proteolytic interaction of NSP5 with HDAC2 and IRF3 [66]. Further demonstrating that cleavage is not required for this interaction, the catalytically inactive NSP5 H41A and NSP5 C145S point mutants maintained their interaction with HDAC2 and had the same suppressive effect on CIITA pI and MHC II promoter activity as wild-type NSP5.…”

“…Although poorly expressed, the rare cells expressing NSP5 deletion mutants lacking the proteolytic (NSP5 Δ1-192 ) or B′ (NSP5 Δ199-306 ) domains displayed a hyper-nuclear localization compared to wild-type, but also had no impact on the distribution of HDAC2, indicating that HDAC2 unlikely to be the protein used by NSP5 to gain access to the nucleus (Figure 5C-D). Naik et al demonstrated that NSP5 can interact with IRF3, and IRF3 is known to bind to the CIITA PI promoter, suggesting that NSP5 may deliver HDAC2 to the CIITA promoter via interactions with IRF3 [66][67][68]. Using FISH-FRET analysis of A549 cells-a type II human alveolar lung epithelial cell line-we found that IFNγ stimulation increased CIITA PI, PIII/IV and MHC II promoter acetylation, and as expected, NSP5 expression inhibited promoter acetylation (Figures 5E-G, S4).…”

The main protease of SARS-CoV-2 cleaves histone deacetylases and DCP1A, attenuating the immune defense of the interferon-stimulated genes

“…4 F). A recent study claimed that SARS-CoV-2 M pro interacts with HDAC2 but M pro inhibits the expression of IFNβ gene and interferon-signaling pathway in an HDAC2-independent manner ( 70 ). However, cleavage of HDAC1/2 by M pro observed in our experiments negatively affects INF-α-stimulated ISG production.…”

SADS‐CoV nsp1 inhibits the IFN‐β production by preventing TBK1 phosphorylation and inducing CBP degradation

“…Porcine deltacoronavirus (PDCoV) nsp5 cleaves the NF‐κB essential modulator (NEMO) to inhibit SeV‐induced IFN‐β production 28 . SARS‐CoV‐2 nsp5 has been reported to induce IRF3 degradation to prevent IFN‐β production 29 . The papain‐like protease (PLpro) has multiple mechanisms for antagonizing the type I interferon pathway 30 .…”

“…28 SARS-CoV-2 nsp5 has been reported to induce IRF3 degradation to prevent IFN-β production. 29 The papain-like protease (PLpro) has multiple mechanisms for antagonizing the type I interferon pathway. 30 The PLpro of SARS-CoV blocks the Toll-like receptor 7 (TLR7) signaling pathway by inhibiting polyubiquitination of TRAF3 and TRAF6.…”