Influenza virus NS1 protein binds cellular DNA to block transcription of antiviral genes

Anastasina, Maria; May, Nicolas Le; Бугай, А. Н.; Fu, Yu; Söderholm, Sandra; Gaelings, Lana; Öhman, Tiina; Tynell, Janne; Kyttanen, Suvi; Barborič, Matjaž; Nyman, Tuula A.; Matikainen, Sampsa; Julkunen, Ilkka; Butcher, Sarah J.; Egly, Jean‐Marc; Kainov, Denis E.

doi:10.1016/j.bbagrm.2016.09.005

Cited by 31 publications

(39 citation statements)

References 55 publications

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“…In particular, we used WSN strains with mutations in the RNA‐binding domain (RBD, R38A/K41A), the effector domain (ED, F103S/M106I and A149V) or the C‐terminal region (Δ221–230) of NS1 . It was shown that these mutations prevent NS1 interactions with dsRNA/DNA, CPSF4, nuclear export machinery or some other cellular and viral factors, and thus suppress the production of IFNs and ISGs . Figure B demonstrates that mutant viruses similar to wild‐type strain reduced the viability of macrophages.…”

Section: Resultsmentioning

confidence: 99%

Regulation of kynurenine biosynthesis during influenza virus infection

et al. 2016

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Influenza A viruses (IAVs) remain serious threats to public health because of the shortage of effective means of control. Developing more effective virus control modalities requires better understanding of virus-host interactions. It has previously been shown that IAV induces the production of kynurenine, which suppresses T-cell responses, enhances pain hypersensitivity and disturbs behaviour in infected animals. However, the regulation of kynurenine biosynthesis during IAV infection remains elusive. Here we showed that IAV infection induced expression of interferons (IFNs), which upregulated production of indoleamine-2,3-dioxygenase (IDO1), which catalysed the kynurenine biosynthesis. Furthermore, IAV attenuated the IDO1 expression and the production of kynurenine through its NS1 protein. Interestingly, inhibition of viral replication prior to IFN induction limited IDO1 expression, while inhibition after did not. Finally, we showed that kynurenine biosynthesis was activated in macrophages in response to other stimuli, such as influenza B virus, herpes simplex virus 1 and 2 as well as bacterial lipopolysaccharides. Thus, the tight regulation of the kynurenine biosynthesis by host cell and, perhaps, pathogen might be a basic signature of a wide range of host-pathogen interactions, which should be taken into account during development of novel antiviral and antibacterial drugs.

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Section: Resultsmentioning

confidence: 99%

Regulation of kynurenine biosynthesis during influenza virus infection

et al. 2016

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“…This could explain why attenuation of the IFN antagonistic ability of NS1-K108R is independent of RIG-I CARD, TBK-1, and IRF3 activation. In addition, Anastasina et al [41] reported that the NS1 protein binds to cellular DNA to block the cellular transcription of IFNs and ISGs; thus, NS1 proteins retained in the cytoplasm lose their cellular DNA binding function, resulting in impaired IFN-β antagonistic ability.…”

Section: Discussionmentioning

confidence: 99%

Acetylation at K108 of the NS1 protein is important for the replication and virulence of influenza virus

et al. 2020

Vet Res

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Non-structural protein 1 (NS1) of influenza virus is a multifunctional protein that plays an important role in virus replication and virulence. In this study, an acetylation modification was identified at the K108 residue of the NS1 protein of H1N1 influenza virus. To further explore the function of the K108 acetylation modification of the NS1 protein, a deacetylation-mimic mutation (K108R) and a constant acetylation-mimic mutation (K108Q) were introduced into the NS1 protein in the background of A/WSN/1933 H1N1 (WSN), resulting in two mutant viruses (WSN-NS1-108R and WSN-NS1-108Q). In vitro and mouse studies showed that the deacetylation-mimic mutation K108R in the NS1 protein attenuated the replication and virulence of WSN-NS1-108R, while the constant acetylation-mimic mutant virus WSN-NS1-108Q showed similar replication and pathogenicity as the wild-type WSN virus (WSN-wt). The results indicated that acetylation at K108 of the NS1 protein has an important role in the replication and virulence of influenza virus. To further explore the potential mechanism, the type I interferon (IFN-I) antagonistic activity of the three NS1 proteins (NS1-108Q, NS1-108R, and NS1-wt) was compared in cells, which showed that the K108R mutation significantly attenuated the IFN-β antagonistic activity of the NS1 protein compared with NS1-wt and NS1-108Q. Both NS1-wt and NS1-108Q inhibited the IFN-β response activated by RIG-I CARD domain, MAVS, TBK1, and IRF3 more efficiently than the NS1-108R protein in cells. Taken together, the results indicated that acetylation at NS1 K108 is important for the IFN antagonistic activity of the NS1 protein and virulence of the influenza virus. © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article' s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article' Publisher's NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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“…These compounds (ABT-737, ABT-263, ABT-199, WEHI-539, A-1331852, A-1155463) have different affinities for Bcl-2 proteins [40], but all can universally induce premature death of IAVinfected cells at concentrations not toxic for non-infected cells [44] (Bulanova et al, unpublished). However, only ABT-263, A-1331852 and A-1155463 could effectively limit viral replication and spread.…”

Section: Bcl-2 Inhibitors As Antiviral Compoundsmentioning

confidence: 99%

“…Other cellular proteins including UACA, PAWR, FLII, Trim21, IMMT, 14-3-3, EFHD2, DHX9, DDX3, NLRP3 and LRRFIP2 as well as viral factors M2, PB1-F2, NS1, HA and NP may play important roles in Bcl-2-dependent apoptosis by stabilizing or altering the interactions of BH3-domain proteins in infected cells [44,[46][47][48]. However, further studies are required to verify their specific functions in apoptosis.…”

Section: Apoptosis In Iav-infected Cellsmentioning

confidence: 99%

“…During this process, PRRs including RIG-I, MDA5, PKR (encoded by ISGs: IFIH1, DDX58 and EIF2AK2) recognize accumulating vRNA and activate pro-apoptotic apoptotic machinery that direct the fate of IAV-infected cells [40]. The anti-apoptotic (Bcl-2, Bcl-xL, and Bcl-w) and pro-apoptotic (Bax, Bak, Bad, Bim, Bid, Puma, and Noxa) Bcl-2 proteins dissociate/associate to start a cascade of reactions leading to mitochondria membrane permeabilization (MOMP), followed by cytochrome C release, apoptosome activation, ATP degradation and eventually cell death [41][42][43][44]. As the initial trigger of this process, concentration of vRNA is therefore a critical rate-limiting factor in apoptosis.…”

Section: Apoptosis In Iav-infected Cellsmentioning

confidence: 99%

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Influenza virus infection, interferon response, viral counter-response and apoptosis

Shim¹,

Kim²,

Min³

et al. 2017

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Human influenza A viruses (IAVs) cause global pandemics and epidemics, which remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral outbreaks, new treatments are urgently needed. Developing new virus control modalities requires better understanding of virus-host interactions. Here we describe how IAV infection triggers cellular apoptosis, and how this process can be exploited towards development of new therapeutics, which might be more effective than the currently available anti-influenza drugs.

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Influenza virus NS1 protein binds cellular DNA to block transcription of antiviral genes

Cited by 31 publications

References 55 publications

Regulation of kynurenine biosynthesis during influenza virus infection

Regulation of kynurenine biosynthesis during influenza virus infection

Acetylation at K108 of the NS1 protein is important for the replication and virulence of influenza virus

Influenza virus infection, interferon response, viral counter-response and apoptosis

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