SARS-CoV-2 Nsp14 mediates the effects of viral infection on the host cell transcriptome

Zaffagni, Michela; Harris, Jenna M; Patop, Inés Lucía; Pamudurti, Nagarjuna Reddy; Nguyen, Sinead; Kadener, Sebastián

doi:10.7554/elife.71945

Cited by 31 publications

(23 citation statements)

References 90 publications

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“…Activation of the NF-κB pathway is closely associated with SASR-CoV-2-induced acute inflammation or the expression of senescence-associated inflammatory factors (Goel et al 2021 ; Zaffagni et al 2022 ). We further studied the activity of NF-κB in S-protein-treated ARPE-19 cells by using immunofluorescence and immunoblotting assays.…”

Section: Resultsmentioning

confidence: 99%

SARS-COV-2 spike protein promotes RPE cell senescence via the ROS/P53/P21 pathway

et al. 2023

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SARS-Cov-2 infection, which has caused the COVID-19 global pandemic, triggers cellular senescence. In this study, we investigate the role of the SARS-COV-2 spike protein (S-protein) in regulating the senescence of RPE cells. The results showed that administration or overexpression of S-protein in ARPE-19 decreased cell proliferation with cell cycle arrest at the G1 phase. S-protein increased SA-β-Gal positive ARPE-19 cells with high expression of P53 and P21, senescence-associated inflammatory factors (e.g., IL-1β, IL-6, IL-8, ICAM, and VEGF), and ROS. Elimination of ROS by N-acetyl cysteine (NAC) or knocking down p21 by siRNA diminished S-protein-induced ARPE cell senescence. Both administrated and overexpressed S-protein colocalize with the ER and upregulate ER-stress-associated BIP, CHOP, ATF3, and ATF6 expression. S-protein induced P65 protein nuclear translocation. Inhibition of NF-κB by bay-11-7082 reduced S-protein-mediated expression of senescence-associated factors. Moreover, the intravitreal injection of S-protein upregulates senescence-associated inflammatory factors in the zebrafish retina. In conclusions, the S-protein of SARS-Cov-2 induces cellular senescence of ARPE-19 cells in vitro and the expression of senescence-associated cytokines in zebrafish retina in vivo likely by activating ER stress, ROS, and NF-κb. These results may uncover a potential association between SARS-cov-2 infection and development of AMD.

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Section: Resultsmentioning

confidence: 99%

SARS-COV-2 spike protein promotes RPE cell senescence via the ROS/P53/P21 pathway

et al. 2023

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“…Further contributing to this hostile cellular takeover is the targeted inhibition of host translation and RNA splicing mediated by Nsp10 and Nsp14 (refs. 124 , 125 ). However, even with these potent viral countermeasures in place, SARS-CoV-2 ultimately induces cell death through multiple mechanisms 126 , enabling detection of the virus by phagocytic cells 127 .…”

Section: Sars-cov-2 Evasion Of Host Defencesmentioning

confidence: 99%

“…Similar interference with global host expression that has also been found to impact splicing has been reported for Nsp10 and Nsp14 (refs. 124 , 125 ). Perturbations in host splicing activity as a result of SARS-CoV-2 infection have been observed in infected lung samples from patients with COVID-19 (ref.…”

Section: Sars-cov-2 Evasion Of Host Defencesmentioning

confidence: 99%

Innate immune evasion strategies of SARS-CoV-2

2023

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SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has been associated with substantial global morbidity and mortality. Despite a tropism that is largely confined to the airways, COVID-19 is associated with multiorgan dysfunction and long-term cognitive pathologies. A major driver of this biology stems from the combined effects of virus-mediated interference with the host antiviral defences in infected cells and the sensing of pathogen-associated material by bystander cells. Such a dynamic results in delayed induction of type I and III interferons (IFN-I and IFN-III) at the site of infection, but systemic IFN-I and IFN-III priming in distal organs and barrier epithelial surfaces, respectively. In this Review, we examine the relationship between SARS-CoV-2 biology and the cellular response to infection, detailing how antagonism and dysregulation of host innate immune defences contribute to disease severity of COVID-19.

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“…Such ExoN role of nsp14 during SARS‐CoV‐2 infections has yet to be explored. In addition, the nsp14 mutants partially inhibited the host's innate immune response by downregulating the expression of interferon‐beta (IFN‐β), and tumor necrosis factor (TNF) expression, by modulating Nuclear factor kappa B (NFkB) signaling pathway and by increasing the number of circular RNAs (circRNAs) 9,10 . The impacts of such nsp14‐mediated functions on the SARS‐CoV‐2 genome evolution and transcriptome functions have to be explored.…”

Section: Mechanisms Involved In the Induction Of Mutations In The Sar...mentioning

confidence: 99%

Perceptions into causes and consequences of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants

Laxminarayana¹

2023

Rheumatology & Autoimmunity

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are emerging worldwide and pathogenicity varies widely from no symptoms to death. The SARS-CoV-2 is evolving as lineages like Alpha, Beta, Gamma, Epsilon, Iota, Delta, and Omicron in the course of time. The main reasons for such viral evolution are (a) the imperfect nature of SARS-CoV-2 RNA polymerase, and viral exonuclease mediated proofreading functions resulting in the generation of mutations in viral genomes; (b) fusions of the 5′ leader sequence to unexpected 3′ sites, and transcription regulatory sequences (TRSs) in subgenomic RNAs (sgRNAs), which result in the generation of structural variants and novel open reading frames; (c) these viruses are combated by the host type I interferons (IFNs). In such a process IFNs upregulate viral RNA editing APOBEC3G/F and ADAR1 genes, which induce mutations in viral genomes. These factors play important roles in causing viral evolution and the emergence of more efficient SARS-CoV-2 genomes, which escape the host immune defense system, and vaccine-elicited antibodies and impede therapeutic strategies. The main challenges we now face are how to control future SARS-CoV-2 evolution, the elimination of their deleterious side effects, and the onset of new diseases as aftermaths of SARS-CoV-2 infections. Preventive measures like (a) the development of broadly neutralizing antibodies and novel vaccines, therapies based on genomics and proteomics data will help in avoiding, and/or minimizing SARS-CoV-2 infections; (b) targeted therapies, application of patient-based precision medicine methodology can help in achieving the goal and avoiding unwanted deleterious side effects and the onset of SARS-CoV-2 infections mediated several diseases in future.gene regulation, innate immunity, mutations, RNA editing enzymes, SARS-CoV-2 pathogenesis, type I interferons Highlights• The molecular mechanisms involved in viral evolution are enlightened. Such information will help to better understand the root causes for the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, their pathophysiology, and the mechanism(s) of infection. • Precision medicine-based strategies may help to eliminate and/or minimize the onset of future aftermaths of SARS-CoV-2 infections and their deleterious effects.

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SARS-CoV-2 Nsp14 mediates the effects of viral infection on the host cell transcriptome

Cited by 31 publications

References 90 publications

SARS-COV-2 spike protein promotes RPE cell senescence via the ROS/P53/P21 pathway

SARS-COV-2 spike protein promotes RPE cell senescence via the ROS/P53/P21 pathway

Innate immune evasion strategies of SARS-CoV-2

Perceptions into causes and consequences of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants

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