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

Liu, Song; Wang, Dianbing; Abbas, Ghulam; Li, Min; Cui, Meng‐Meng; Wang, Jufang; Lin, Zhanglin; Zhang, Xian-En

doi:10.1016/j.jbc.2023.102990

Cited by 14 publications

(14 citation statements)

References 83 publications

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“…IFN-I classically activates JAK kinase (Tyk-2 and JAK1) and STAT proteins (STAT-1 and 2) through interaction with their specific membrane receptor [53]. However, abnormalities in the IFN-signaling cascade have been reported in SARS-CoV-2 infection, which may lead to the failure of ISG activation [23,[53][54][55]. Nsp5 has been shown to inhibit ISG induction by cleaving histone deacetylases [54], Nsp6 blocks IRF3 activation and inhibits STAT-1 and 2 tyrosine phosphorylation, while Nsp12 inhibits IRF3 nuclear translocation.…”

Section: Discussionmentioning

confidence: 99%

Age‐related transcript changes in type I interferon signaling in children and adolescents with long COVID

Fracella,

Mancino,

Nenna

et al. 2024

Eur J Immunol

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SARS‐CoV‐2 typically causes mild symptoms in children, but evidence suggests that persistent immunopathological changes may lead to long COVID (LC). To explore the interplay between LC and innate immunity, we assessed the type I interferon (IFN‐I) response in children and adolescents with LC symptoms (LC; n = 28). This was compared with age‐matched SARS‐CoV‐2 recovered participants without LC symptoms (MC; n = 28) and healthy controls (HC; n = 18). We measured the mRNA expression of IFN‐I (IFN‐α/β/ε/ω), IFN‐I receptor (IFNAR1/2), and ISGs (ISG15, ISG56, MxA, IFI27, BST2, LY6E, OAS1, OAS2, OAS3, and MDA5) in PBMCs collected 3–6 months after COVID‐19. LC adolescents (12–17 years) had higher transcript levels of IFN‐β, IFN‐ε, and IFN‐ω than HC, whereas LC children (6–11 years) had lower levels than HC. In adolescents, increased levels of IFN‐α, IFN‐β, and IFN‐ω mRNAs were found in the LC group compared with MC, while lower levels were observed in LC children than MC. Adolescents with neurological symptoms had higher IFN‐α/β mRNA levels than MC. LC and MC participants showed decreased expression of ISGs and IFNAR1, but increased expression of IFNAR2, than HC. Our results show age‐related changes in the expression of transcripts involved in the IFN‐I signaling pathway in children and adolescents with LC.

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Section: Discussionmentioning

confidence: 99%

Age‐related transcript changes in type I interferon signaling in children and adolescents with long COVID

Fracella,

Mancino,

Nenna

et al. 2024

Eur J Immunol

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“…Downward, only the residue appears to be governing the cleavage selectivity as it can only be a serine, an alanine or an asparagine. 7 Concerning host cell proteins, quite a few 8–11 have been reported as substrates of SARS-CoV-2 M pro , thus providing further insights into the many ways 12,13 viruses play havoc in cellular biochemistry and innate immunity. A recent review on the proteins reported as substrates of this protease is also available.…”

Section: Introductionmentioning

confidence: 99%

On the origins of SARS-CoV-2 main protease inhibitors

Janin

2024

RSC Med. Chem.

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“…It is responsible for 11 cleavage sites in the viral polyproteins to release 12 NSPs, including itself (NSP5), RNA‐dependent RNA polymerase (RdRp, NSP12), and helicase (NSP13) 8 . In addition, Mpro cleaves histone deacetylases (HDACs) to attenuate host innate immune response of interferon‐stimulated genes (ISGs) 9 . Due to its essential role in virus replication and host immune evasion, Mpro has been regarded as a viable drug target for developing antivirals 10–12 …”

Section: Introductionmentioning

confidence: 99%

“…histone deacetylases (HDACs) to attenuate host innate immune response of interferon-stimulated genes (ISGs). 9 Due to its essential role in virus replication and host immune evasion, Mpro has been regarded as a viable drug target for developing antivirals. [10][11][12] As a gold standard assay, the fluorescence resonance energy transfer (FRET) assay has been widely used for high-throughput screening (HTS) of Mpro inhibitors.…”

mentioning

confidence: 99%

Improved fluorescence‐based assay for rapid screening and evaluation of SARS‐CoV‐2 main protease inhibitors

Zhang,

Yan,

Zhou

et al. 2024

Journal of Medical Virology

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The outbreak of coronavirus disease 2019 (COVID‐19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a global threat to human health. In parallel with vaccines, efficacious antivirals are urgently needed. SARS‐CoV‐2 main protease (Mpro) is an attractive drug target for antiviral development owing to its key roles in virus replication and host immune evasion. Due to the limitations of currently available methods, the development of novel high‐throughput screening assays is of the highest importance for the discovery of Mpro inhibitors. In this study, we first developed an improved fluorescence‐based assay for rapid screening of Mpro inhibitors from an anti‐infection compound library using a versatile dimerization‐dependent red fluorescent protein (ddRFP) biosensor. Utilizing this assay, we identified MG‐101 as a competitive Mpro inhibitor in vitro. Moreover, our results revealed that ensitrelvir is a potent Mpro inhibitor, but baicalein, chloroquine, ebselen, echinatin, and silibinin are not. Therefore, this robust ddRFP assay provides a faithful avenue for rapid screening and evaluation of Mpro inhibitors to fight against COVID‐19.

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

Cited by 14 publications

References 83 publications

Age‐related transcript changes in type I interferon signaling in children and adolescents with long COVID

Age‐related transcript changes in type I interferon signaling in children and adolescents with long COVID

On the origins of SARS-CoV-2 main protease inhibitors

Improved fluorescence‐based assay for rapid screening and evaluation of SARS‐CoV‐2 main protease inhibitors

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