Species-specific inhibition of RIG-I ubiquitination and IFN induction by the influenza A virus NS1 protein.

Influenza A viruses can adapt to new host species, leading to the emergence of novel pathogenic strains. There is evidence that highly pathogenic viruses encode for non-structural 1 (NS1) proteins that are more efficient in suppressing the host immune response. The NS1 protein inhibits type-I interf...

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Autores principales: Ricardo Rajsbaum, Randy A Albrecht, May K Wang, Natalya P Maharaj, Gijs A Versteeg, Estanislao Nistal-Villán, Adolfo García-Sastre, Michaela U Gack
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Publicado: Public Library of Science (PLoS) 2012
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Acceso en línea:https://doaj.org/article/68e798ffdedb4154898c30314604fbb4
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spelling oai:doaj.org-article:68e798ffdedb4154898c30314604fbb42021-11-18T06:06:18ZSpecies-specific inhibition of RIG-I ubiquitination and IFN induction by the influenza A virus NS1 protein.1553-73661553-737410.1371/journal.ppat.1003059https://doaj.org/article/68e798ffdedb4154898c30314604fbb42012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23209422/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Influenza A viruses can adapt to new host species, leading to the emergence of novel pathogenic strains. There is evidence that highly pathogenic viruses encode for non-structural 1 (NS1) proteins that are more efficient in suppressing the host immune response. The NS1 protein inhibits type-I interferon (IFN) production partly by blocking the TRIM25 ubiquitin E3 ligase-mediated Lys63-linked ubiquitination of the viral RNA sensor RIG-I, required for its optimal downstream signaling. In order to understand possible mechanisms of viral adaptation and host tropism, we examined the ability of NS1 encoded by human (Cal04), avian (HK156), swine (SwTx98) and mouse-adapted (PR8) influenza viruses to interact with TRIM25 orthologues from mammalian and avian species. Using co-immunoprecipitation assays we show that human TRIM25 binds to all tested NS1 proteins, whereas the chicken TRIM25 ortholog binds preferentially to the NS1 from the avian virus. Strikingly, none of the NS1 proteins were able to bind mouse TRIM25. Since NS1 can inhibit IFN production in mouse, we tested the impact of TRIM25 and NS1 on RIG-I ubiquitination in mouse cells. While NS1 efficiently suppressed human TRIM25-dependent ubiquitination of RIG-I 2CARD, NS1 inhibited the ubiquitination of full-length mouse RIG-I in a mouse TRIM25-independent manner. Therefore, we tested if the ubiquitin E3 ligase Riplet, which has also been shown to ubiquitinate RIG-I, interacts with NS1. We found that NS1 binds mouse Riplet and inhibits its activity to induce IFN-β in murine cells. Furthermore, NS1 proteins of human but not swine or avian viruses were able to interact with human Riplet, thereby suppressing RIG-I ubiquitination. In conclusion, our results indicate that influenza NS1 protein targets TRIM25 and Riplet ubiquitin E3 ligases in a species-specific manner for the inhibition of RIG-I ubiquitination and antiviral IFN production.Ricardo RajsbaumRandy A AlbrechtMay K WangNatalya P MaharajGijs A VersteegEstanislao Nistal-VillánAdolfo García-SastreMichaela U GackPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 8, Iss 11, p e1003059 (2012)
institution DOAJ
collection DOAJ
language EN
topic Immunologic diseases. Allergy
RC581-607
Biology (General)
QH301-705.5
spellingShingle Immunologic diseases. Allergy
RC581-607
Biology (General)
QH301-705.5
Ricardo Rajsbaum
Randy A Albrecht
May K Wang
Natalya P Maharaj
Gijs A Versteeg
Estanislao Nistal-Villán
Adolfo García-Sastre
Michaela U Gack
Species-specific inhibition of RIG-I ubiquitination and IFN induction by the influenza A virus NS1 protein.
description Influenza A viruses can adapt to new host species, leading to the emergence of novel pathogenic strains. There is evidence that highly pathogenic viruses encode for non-structural 1 (NS1) proteins that are more efficient in suppressing the host immune response. The NS1 protein inhibits type-I interferon (IFN) production partly by blocking the TRIM25 ubiquitin E3 ligase-mediated Lys63-linked ubiquitination of the viral RNA sensor RIG-I, required for its optimal downstream signaling. In order to understand possible mechanisms of viral adaptation and host tropism, we examined the ability of NS1 encoded by human (Cal04), avian (HK156), swine (SwTx98) and mouse-adapted (PR8) influenza viruses to interact with TRIM25 orthologues from mammalian and avian species. Using co-immunoprecipitation assays we show that human TRIM25 binds to all tested NS1 proteins, whereas the chicken TRIM25 ortholog binds preferentially to the NS1 from the avian virus. Strikingly, none of the NS1 proteins were able to bind mouse TRIM25. Since NS1 can inhibit IFN production in mouse, we tested the impact of TRIM25 and NS1 on RIG-I ubiquitination in mouse cells. While NS1 efficiently suppressed human TRIM25-dependent ubiquitination of RIG-I 2CARD, NS1 inhibited the ubiquitination of full-length mouse RIG-I in a mouse TRIM25-independent manner. Therefore, we tested if the ubiquitin E3 ligase Riplet, which has also been shown to ubiquitinate RIG-I, interacts with NS1. We found that NS1 binds mouse Riplet and inhibits its activity to induce IFN-β in murine cells. Furthermore, NS1 proteins of human but not swine or avian viruses were able to interact with human Riplet, thereby suppressing RIG-I ubiquitination. In conclusion, our results indicate that influenza NS1 protein targets TRIM25 and Riplet ubiquitin E3 ligases in a species-specific manner for the inhibition of RIG-I ubiquitination and antiviral IFN production.
format article
author Ricardo Rajsbaum
Randy A Albrecht
May K Wang
Natalya P Maharaj
Gijs A Versteeg
Estanislao Nistal-Villán
Adolfo García-Sastre
Michaela U Gack
author_facet Ricardo Rajsbaum
Randy A Albrecht
May K Wang
Natalya P Maharaj
Gijs A Versteeg
Estanislao Nistal-Villán
Adolfo García-Sastre
Michaela U Gack
author_sort Ricardo Rajsbaum
title Species-specific inhibition of RIG-I ubiquitination and IFN induction by the influenza A virus NS1 protein.
title_short Species-specific inhibition of RIG-I ubiquitination and IFN induction by the influenza A virus NS1 protein.
title_full Species-specific inhibition of RIG-I ubiquitination and IFN induction by the influenza A virus NS1 protein.
title_fullStr Species-specific inhibition of RIG-I ubiquitination and IFN induction by the influenza A virus NS1 protein.
title_full_unstemmed Species-specific inhibition of RIG-I ubiquitination and IFN induction by the influenza A virus NS1 protein.
title_sort species-specific inhibition of rig-i ubiquitination and ifn induction by the influenza a virus ns1 protein.
publisher Public Library of Science (PLoS)
publishDate 2012
url https://doaj.org/article/68e798ffdedb4154898c30314604fbb4
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