NS5 Conservative Site Is Required for Zika Virus to Restrict the RIG-I Signaling

Li, Aixin; Wang, Wenbiao; Wang, Yingchong; Chen, Keli; Xiao, Feng; Hu, Dingwen; Hui, Lixia; Liu, Weiyong; Feng, Yuqian; Li, Geng; Tan, Qiuping; Liu, Yingle; Wu, Kailang; Wu, Jianguo

doi:10.3389/fimmu.2020.00051

Cited by 35 publications

(37 citation statements)

References 45 publications

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“…It is now important to identify the precise mechanisms by which the RLR signaling cascade is targeted by NS5. Recently, Li et al described that NS5 directly represses K63-linked polyubiquitination of RIG-I [ 61 ]. In addition, an inhibitory effect of NS5 on IRF3 activation has been suggested [ 44 , 62 , 63 ].…”

Section: Discussionmentioning

confidence: 99%

RIG-I Plays a Dominant Role in the Induction of Transcriptional Changes in Zika Virus-Infected Cells, which Protect from Virus-Induced Cell Death

Schilling

Bridgeman

Gray

et al. 2020

Cells

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The Zika virus (ZIKV) has received much attention due to an alarming increase in cases of neurological disorders including congenital Zika syndrome associated with infection. To date, there is no effective treatment available. An immediate response by the innate immune system is crucial for effective control of the virus. Using CRISPR/Cas9-mediated knockouts in A549 cells, we investigated the individual contributions of the RIG-I-like receptors MDA5 and RIG-I to ZIKV sensing and control of this virus by using a Brazilian ZIKV strain. We show that RIG-I is the main sensor for ZIKV in A549 cells. Surprisingly, we observed that loss of RIG-I and consecutive type I interferon (IFN) production led to virus-induced apoptosis. ZIKV non-structural protein NS5 was reported to interfere with type I IFN receptor signaling. Additionally, we show that ZIKV NS5 inhibits type I IFN induction. Overall, our study highlights the importance of RIG-I-dependent ZIKV sensing for the prevention of virus-induced cell death and shows that NS5 inhibits the production of type I IFN.

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Section: Discussionmentioning

confidence: 99%

RIG-I Plays a Dominant Role in the Induction of Transcriptional Changes in Zika Virus-Infected Cells, which Protect from Virus-Induced Cell Death

Schilling

Bridgeman

Gray

et al. 2020

Cells

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“…The primer sequences were as follows: IFN-β forward: 5′-TGGGAGGCTTGAATACTGCCTCAA-3′; and IFN-β reverse: 5′-TCCTTGGCCTTCAGGTAATGCAGA-3′, the amplicon size: 336 [ 31 ]. GAPDH forward: 5′-ATGACATCAAGAAGGTGGTG-3′; GAPDH reverse: 5′-CATACCAGGAAATGAGCTTG-3′, the amplicon size: 179 [ 32 ].…”

Section: Methodsmentioning

confidence: 99%

SARS-CoV-2 Nucleocapsid Protein Interacts with RIG-I and Represses RIG-Mediated IFN-β Production

Chen

Xiao

et al. 2020

Viruses

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SARS-CoV-2 is highly pathogenic in humans and poses a great threat to public health worldwide. Clinical data shows a disturbed type I interferon (IFN) response during the virus infection. In this study, we discovered that the nucleocapsid (N) protein of SARS-CoV-2 plays an important role in the inhibition of interferon beta (IFN-β) production. N protein repressed IFN-β production induced by poly(I:C) or upon Sendai virus (SeV) infection. We noted that N protein also suppressed IFN-β production, induced by several signaling molecules downstream of the retinoic acid-inducible gene I (RIG-I) pathway, which is the crucial pattern recognition receptor (PRR) responsible for identifying RNA viruses. Moreover, our data demonstrated that N protein interacted with the RIG-I protein through the DExD/H domain, which has ATPase activity and plays an important role in the binding of immunostimulatory RNAs. These results suggested that SARS-CoV-2 N protein suppresses the IFN-β response through targeting the initial step, potentially the cellular PRR–RNA-recognition step in the innate immune pathway. Therefore, we propose that the SARS-CoV-2 N protein represses IFN-β production by interfering with RIG-I.

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“…NS5 targets each level of the IFN activation axis in host cells, particularly impairing genomic RNA sensing at its 5′ untranslated region (UTR) capping by RIG-I by repressing RIG-I polyubiquitination by means of the NS5-MTase (methyltransferase) domain but MTase function independent, thereby making RIG-I incompetent to activate IRF3 and therefore IFN-β production [ 241 ], or by acting as a barrier of IFN activation ( Figure 1 ). Hence, NS5 abrogates IRF3 and NF-κB signaling [ 234 ], as it is able to interact with IRF3 avoiding its activation [ 224 ], or binding to IKKε, affecting IKKε protein levels and phosphorylation, which also finally results in IRF3 inactivation [ 242 ].…”

Section: Mechanisms Of Zikv Immune Evasionmentioning

confidence: 99%

Zika Virus Pathogenesis: A Battle for Immune Evasion

et al. 2021

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Zika virus (ZIKV) infection and its associated congenital and other neurological disorders, particularly microcephaly and other fetal developmental abnormalities, constitute a World Health Organization (WHO) Zika Virus Research Agenda within the WHO’s R&D Blueprint for Action to Prevent Epidemics, and continue to be a Public Health Emergency of International Concern (PHEIC) today. ZIKV pathogenicity is initiated by viral infection and propagation across multiple placental and fetal tissue barriers, and is critically strengthened by subverting host immunity. ZIKV immune evasion involves viral non-structural proteins, genomic and non-coding RNA and microRNA (miRNA) to modulate interferon (IFN) signaling and production, interfering with intracellular signal pathways and autophagy, and promoting cellular environment changes together with secretion of cellular components to escape innate and adaptive immunity and further infect privileged immune organs/tissues such as the placenta and eyes. This review includes a description of recent advances in the understanding of the mechanisms underlying ZIKV immune modulation and evasion that strongly condition viral pathogenesis, which would certainly contribute to the development of anti-ZIKV strategies, drugs, and vaccines.

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NS5 Conservative Site Is Required for Zika Virus to Restrict the RIG-I Signaling

Cited by 35 publications

References 45 publications

RIG-I Plays a Dominant Role in the Induction of Transcriptional Changes in Zika Virus-Infected Cells, which Protect from Virus-Induced Cell Death

RIG-I Plays a Dominant Role in the Induction of Transcriptional Changes in Zika Virus-Infected Cells, which Protect from Virus-Induced Cell Death

SARS-CoV-2 Nucleocapsid Protein Interacts with RIG-I and Represses RIG-Mediated IFN-β Production

Zika Virus Pathogenesis: A Battle for Immune Evasion

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