Main protease of SARS-CoV-2 serves as a bifunctional molecule in restricting type I interferon antiviral signaling

Wu, Yiming; Ma, Ling; Zhuang, Zhen; Cai, Sihui; Zhao, Zhiyao; Zhou, Lingli; Zhang, Jing; Wang, Pei‐Hui; Zhao, Jincun; Cui, Jun

doi:10.1038/s41392-020-00332-2

Cited by 85 publications

(105 citation statements)

References 5 publications

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“…It is also suggested that 3CL pro could promote autophagic degradation of STAT1. In conditions where 3CL pro was seen to be expressed in high amounts, the viral replication was enhanced due to the reduction in IFN and ISG signaling pathways [ 74 ]. The PL pro also houses de-ubiquitination and de- ISGylation properties via the JAK-STAT pathway.…”

Section: Deciphering the Link Between Sars-cov-2 Proteins And Jak/stamentioning

confidence: 99%

JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy

Satarker

Tom²,

Shaji³

et al. 2020

Postgraduate Medicine

137

124

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As the incidence of COVID-19 increases with time, more and more efforts are made to pave a way out for the therapeutic strategies to deal with the disease progression. Inflammation being a significant influencer has implicated us to re-look into its signaling cascades drawing attention towards the JAK/STAT pathway. Considered as a major signaling mediator of cytokines and chemokines, the JAK/STAT pathway has significantly contributed to the worsening of COVID-19. JAK phosphorylation mediated by cytokine receptor activation leads to phosphorylation of STATs that translocate into the nucleus to translate for inflammatory mediators. The SARS-CoV-2 infection triggers the inflammation via the JAK/STAT pathway mainly through its structural and non-structural proteins leading towards the development of cytokine storms. This produces various inflammatory markers in the host that determine the disease severity. Therefore, inhibiting JAK/STAT signaling with JAK/STAT inhibitors like Ruxolitinib, Baricitinib, Tofacitinib could hamper the inflammatory cascade and reduce inflammation. Even though they are implicated with multiple adverse effects, the regulatory authorities have supported its use, and numerous clinical trials are in progress to prove their safety and efficacy. On the contrary, the exact mechanism of JAK/STAT inhibition at molecular levels remains to be speculative for which further investigations are required.

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Section: Deciphering the Link Between Sars-cov-2 Proteins And Jak/stamentioning

confidence: 99%

JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy

Satarker

Tom²,

Shaji³

et al. 2020

Postgraduate Medicine

137

124

View full text Add to dashboard Cite

show abstract

“…Mitochondrial dysfunction-mediated reduced oxygen sensing, and mitochondrial oxidative stress-mediated platelet dysfunction and coagulation pathways have been reported in SARS-CoV-2 infection [ 106 , 107 ]. SARS-CoV-2 main protease Mpro (nsp5) impairs both the virus-induced type I IFN production and the induction of downstream antiviral interferon-stimulated genes (ISGs) [ 108 ]. Another protein, Orf9b, localizes to mitochondria, binds to TOM70, an adaptor protein of the mitochondrial outer membrane, and suppresses the antiviral type I IFN response [ 109 , 110 ].…”

Section: Viral Infections and Mitochondrial Biogenesismentioning

confidence: 99%

Role of Mitochondria in Viral Infections

Elesela

Lukacs

2021

Life

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Viral diseases account for an increasing proportion of deaths worldwide. Viruses maneuver host cell machinery in an attempt to subvert the intracellular environment favorable for their replication. The mitochondrial network is highly susceptible to physiological and environmental insults, including viral infections. Viruses affect mitochondrial functions and impact mitochondrial metabolism, and innate immune signaling. Resurgence of host-virus interactions in recent literature emphasizes the key role of mitochondria and host metabolism on viral life processes. Mitochondrial dysfunction leads to damage of mitochondria that generate toxic compounds, importantly mitochondrial DNA, inducing systemic toxicity, leading to damage of multiple organs in the body. Mitochondrial dynamics and mitophagy are essential for the maintenance of mitochondrial quality control and homeostasis. Therefore, metabolic antagonists may be essential to gain a better understanding of viral diseases and develop effective antiviral therapeutics. This review briefly discusses how viruses exploit mitochondrial dynamics for virus proliferation and induce associated diseases.

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“…NsP5 cleaves STAT2 by targeting two regions on the P1 position of the protein with glutamine residues, an observation used to design biomimetic drugs against this NsP [ 57 , 59 ]. SARS-CoV-2 NsP5 was found to be a relatively more potent inhibitor of IFN-β than SARS-CoV-1 NsP5 by targeting IFN-stimulated response elements (ISRE), NF-kb signaling, K63-linked ubiquitination of RIG-I, and its interaction with its E3 ligase TRIM25 [ 60 ]. Moreover, SARS-CoV-2 NsP5 impaired IFN-mediated STAT-1 phosphorylation by increasing its colocalization with LC3B and hence increasing its autophagic degradation.…”

Section: Immune Response To Sars-cov-2mentioning

confidence: 99%

SARS–CoV-2 Immuno-Pathogenesis and Potential for Diverse Vaccines and Therapies: Opportunities and Challenges

McGill

Kahlil

Dutta

et al. 2021

Infectious Disease Reports

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Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a novel coronavirus that emerged from Wuhan, China in late 2019 causing coronavirus disease-19 (COVID-19). SARS-CoV-2 infection begins by attaching to angiotensin-converting enzyme 2 receptor (ACE2) via the spike glycoprotein, followed by cleavage by TMPRSS2, revealing the viral fusion domain. Other presumptive receptors for SARS-CoV-2 attachment include CD147, neuropilin-1 (NRP1), and Myeloid C-lectin like receptor (CLR), each of which might play a role in the systemic viral spread. The pathology of SARS-CoV-2 infection ranges from asymptomatic to severe acute respiratory distress syndrome, often displaying a cytokine storm syndrome, which can be life-threatening. Despite progress made, the detailed mechanisms underlying SARS-CoV-2 interaction with the host immune system remain unclear and are an area of very active research. The process’s key players include viral non-structural proteins and open reading frame products, which have been implicated in immune antagonism. The dysregulation of the innate immune system results in reduced adaptive immune responses characterized by rapidly diminishing antibody titers. Several treatment options for COVID-19 are emerging, with immunotherapies, peptide therapies, and nucleic acid vaccines showing promise. This review discusses the advances in the immunopathology of SARS-CoV-2, vaccines and therapies under investigation to counter the effects of this virus, as well as viral variants.

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Main protease of SARS-CoV-2 serves as a bifunctional molecule in restricting type I interferon antiviral signaling

Cited by 85 publications

References 5 publications

JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy

JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy

Role of Mitochondria in Viral Infections

SARS–CoV-2 Immuno-Pathogenesis and Potential for Diverse Vaccines and Therapies: Opportunities and Challenges

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