SARS-CoV-2 virus NSP14 Impairs NRF2/HMOX1 activation by targeting Sirtuin 1

Zhang, Shilei; Wang, Jingfeng; Wang, Lulan; Aliyari, Saba R.; Cheng, Genhong

doi:10.1038/s41423-022-00887-w

Cited by 42 publications

(34 citation statements)

References 75 publications

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“…However, due to current technical limitations one remaining question is whether Nsp14 protein expressed from SARS-CoV-2 viral genome truly contributes to NF-κB activation and IL-6/8 induction, which needs future confirmation. A recent study showed that Nsp14 interacts with SIRT1/SIRT5 to decrease NRF2/HMOX1 signaling while increase oxidant stress and inflammatory responses ( 46 ). Nsp14 H268A mutant and other exoribonuclease-deficient mutants still inhibit NRF2/ARE-driven transcription, suggesting that Nsp14 may affect cellular signaling via protein-protein interaction independent of its exoribonuclease activity.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Nsp14 protein associates with IMPDH2 and activates NF-κB signaling

Kenney

Park

et al. 2022

Front. Immunol.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to NF-κB activation and induction of pro-inflammatory cytokines, though the underlying mechanism for this activation is not fully understood. Our results reveal that the SARS-CoV-2 Nsp14 protein contributes to the viral activation of NF-κB signaling. Nsp14 caused the nuclear translocation of NF-κB p65. Nsp14 induced the upregulation of IL-6 and IL-8, which also occurred in SARS-CoV-2 infected cells. IL-8 upregulation was further confirmed in lung tissue samples from COVID-19 patients. A previous proteomic screen identified the putative interaction of Nsp14 with host Inosine-5’-monophosphate dehydrogenase 2 (IMPDH2), which is known to regulate NF-κB signaling. We confirmed the Nsp14-IMPDH2 protein interaction and identified that IMPDH2 knockdown or chemical inhibition using ribavirin (RIB) and mycophenolic acid (MPA) abolishes Nsp14- mediated NF-κB activation and cytokine induction. Furthermore, IMPDH2 inhibitors (RIB, MPA) or NF-κB inhibitors (bortezomib, BAY 11-7082) restricted SARS-CoV-2 infection, indicating that IMPDH2-mediated activation of NF-κB signaling is beneficial to viral replication. Overall, our results identify a novel role of SARS-CoV-2 Nsp14 in inducing NF-κB activation through IMPDH2 to promote viral infection.

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Nsp14 protein associates with IMPDH2 and activates NF-κB signaling

Kenney

Park

et al. 2022

Front. Immunol.

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“…The effect of oxidative stress is not specific to TGEV. According to relevant literature, other coronaviruses (SARS-CoV [ 56 ], SARS-CoV-2 [ 57 , 58 ] and MERS [ 59 ]) can also induce oxidative stress. However, there are no relevant reports showing the effect of eugenol on other coronavirus.…”

Section: Discussionmentioning

confidence: 99%

Eugenol Attenuates Transmissible Gastroenteritis Virus-Induced Oxidative Stress and Apoptosis Via ROS-NRF2-ARE Signaling

Wang

Yan

et al. 2022

Antioxidants

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Transmissible gastroenteritis virus (TGEV), a coronavirus that causes severe diarrhea due to oxidative stress in the piglet intestine, is a major cause of economic loss in the livestock industry. However, limited interventions have been shown to be effective in the treatment of TGEV. Here, we demonstrate the therapeutic activity of eugenol in TGEV-induced intestinal oxidative stress and apoptosis. Our data show that eugenol supplementation protects intestine and IPEC-J2 cells from TGEV-induced damage. Mechanistically, eugenol reduces TGEV-induced oxidative stress in intestinal epithelial cells by reducing reactive oxygen species levels. Interestingly, eugenol also inhibits TGEV-induced intestinal cell apoptosis in vitro and in vivo. In conclusion, our data suggest that eugenol prevents TGEV-induced intestinal oxidative stress by reducing ROS-mediated damage to antioxidant signaling pathways. Therefore, eugenol may be a promising therapeutic strategy for TGEV infection.

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“…5 ). In addition, recently published data show that the HMOX-1 axis is so detrimental for SARS-CoV-2 that it selected for an inhibitory function encoded in the viral Nsp14 protein [ 56 ]. This further supports our argument that herein documented Lamiaceae herb-induced HMOX-1 induction elicits relevant antiviral activity against SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 99%

Identification of herbal teas and their compounds eliciting antiviral activity against SARS-CoV-2 in vitro

et al. 2022

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Background The SARS-CoV-2/COVID-19 pandemic has inflicted medical and socioeconomic havoc, and despite the current availability of vaccines and broad implementation of vaccination programs, more easily accessible and cost-effective acute treatment options preventing morbidity and mortality are urgently needed. Herbal teas have historically and recurrently been applied as self-medication for prophylaxis, therapy, and symptom alleviation in diverse diseases, including those caused by respiratory viruses, and have provided sources of natural products as basis for the development of therapeutic agents. To identify affordable, ubiquitously available, and effective treatments, we tested herbs consumed worldwide as herbal teas regarding their antiviral activity against SARS-CoV-2. Results Aqueous infusions prepared by boiling leaves of the Lamiaceae perilla and sage elicit potent and sustained antiviral activity against SARS-CoV-2 when applied after infection as well as prior to infection of cells. The herbal infusions exerted in vitro antiviral effects comparable to interferon-β and remdesivir but outperformed convalescent sera and interferon-α2 upon short-term treatment early after infection. Based on protein fractionation analyses, we identified caffeic acid, perilla aldehyde, and perillyl alcohol as antiviral compounds. Global mass spectrometry (MS) analyses performed comparatively in two different cell culture infection models revealed changes of the proteome upon treatment with herbal infusions and provided insights into the mode of action. As inferred by the MS data, induction of heme oxygenase 1 (HMOX-1) was confirmed as effector mechanism by the antiviral activity of the HMOX-1-inducing compounds sulforaphane and fraxetin. Conclusions In conclusion, herbal teas based on perilla and sage exhibit antiviral activity against SARS-CoV-2 including variants of concern such as Alpha, Beta, Delta, and Omicron, and we identified HMOX-1 as potential therapeutic target. Given that perilla and sage have been suggested as treatment options for various diseases, our dataset may constitute a valuable resource also for future research beyond virology.

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SARS-CoV-2 virus NSP14 Impairs NRF2/HMOX1 activation by targeting Sirtuin 1

Cited by 42 publications

References 75 publications

SARS-CoV-2 Nsp14 protein associates with IMPDH2 and activates NF-κB signaling

SARS-CoV-2 Nsp14 protein associates with IMPDH2 and activates NF-κB signaling

Eugenol Attenuates Transmissible Gastroenteritis Virus-Induced Oxidative Stress and Apoptosis Via ROS-NRF2-ARE Signaling

Identification of herbal teas and their compounds eliciting antiviral activity against SARS-CoV-2 in vitro

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