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USP22 controls type III interferon signaling and SARS-CoV-2 infection through activation of STING

Pattern recognition receptors (PRRs) and interferons (IFNs) serve as essential antiviral defense against SARS-CoV-2, the causative agent of the COVID-19 pandemic. Type III IFNs (IFN-λ) exhibit cell-type specific and long-lasting functions in auto-inflammation, tumorigenesis, and antiviral defense. H...

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Autores principales: Karlowitz, Rebekka, Stanifer, Megan L., Roedig, Jens, Andrieux, Geoffroy, Bojkova, Denisa, Bechtel, Marco, Smith, Sonja, Kowald, Lisa, Schubert, Ralf, Boerries, Melanie, Cinatl, Jindrich, Boulant, Steeve, van Wijk, Sjoerd J. L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9357023/
https://www.ncbi.nlm.nih.gov/pubmed/35933402
http://dx.doi.org/10.1038/s41419-022-05124-w
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author Karlowitz, Rebekka
Stanifer, Megan L.
Roedig, Jens
Andrieux, Geoffroy
Bojkova, Denisa
Bechtel, Marco
Smith, Sonja
Kowald, Lisa
Schubert, Ralf
Boerries, Melanie
Cinatl, Jindrich
Boulant, Steeve
van Wijk, Sjoerd J. L.
author_facet Karlowitz, Rebekka
Stanifer, Megan L.
Roedig, Jens
Andrieux, Geoffroy
Bojkova, Denisa
Bechtel, Marco
Smith, Sonja
Kowald, Lisa
Schubert, Ralf
Boerries, Melanie
Cinatl, Jindrich
Boulant, Steeve
van Wijk, Sjoerd J. L.
author_sort Karlowitz, Rebekka
collection PubMed
description Pattern recognition receptors (PRRs) and interferons (IFNs) serve as essential antiviral defense against SARS-CoV-2, the causative agent of the COVID-19 pandemic. Type III IFNs (IFN-λ) exhibit cell-type specific and long-lasting functions in auto-inflammation, tumorigenesis, and antiviral defense. Here, we identify the deubiquitinating enzyme USP22 as central regulator of basal IFN-λ secretion and SARS-CoV-2 infections in human intestinal epithelial cells (hIECs). USP22-deficient hIECs strongly upregulate genes involved in IFN signaling and viral defense, including numerous IFN-stimulated genes (ISGs), with increased secretion of IFN-λ and enhanced STAT1 signaling, even in the absence of exogenous IFNs or viral infection. Interestingly, USP22 controls basal and 2′3′-cGAMP-induced STING activation and loss of STING reversed STAT activation and ISG and IFN-λ expression. Intriguingly, USP22-deficient hIECs are protected against SARS-CoV-2 infection, viral replication, and the formation of de novo infectious particles, in a STING-dependent manner. These findings reveal USP22 as central host regulator of STING and type III IFN signaling, with important implications for SARS-CoV-2 infection and antiviral defense.
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spelling pubmed-93570232022-08-08 USP22 controls type III interferon signaling and SARS-CoV-2 infection through activation of STING Karlowitz, Rebekka Stanifer, Megan L. Roedig, Jens Andrieux, Geoffroy Bojkova, Denisa Bechtel, Marco Smith, Sonja Kowald, Lisa Schubert, Ralf Boerries, Melanie Cinatl, Jindrich Boulant, Steeve van Wijk, Sjoerd J. L. Cell Death Dis Article Pattern recognition receptors (PRRs) and interferons (IFNs) serve as essential antiviral defense against SARS-CoV-2, the causative agent of the COVID-19 pandemic. Type III IFNs (IFN-λ) exhibit cell-type specific and long-lasting functions in auto-inflammation, tumorigenesis, and antiviral defense. Here, we identify the deubiquitinating enzyme USP22 as central regulator of basal IFN-λ secretion and SARS-CoV-2 infections in human intestinal epithelial cells (hIECs). USP22-deficient hIECs strongly upregulate genes involved in IFN signaling and viral defense, including numerous IFN-stimulated genes (ISGs), with increased secretion of IFN-λ and enhanced STAT1 signaling, even in the absence of exogenous IFNs or viral infection. Interestingly, USP22 controls basal and 2′3′-cGAMP-induced STING activation and loss of STING reversed STAT activation and ISG and IFN-λ expression. Intriguingly, USP22-deficient hIECs are protected against SARS-CoV-2 infection, viral replication, and the formation of de novo infectious particles, in a STING-dependent manner. These findings reveal USP22 as central host regulator of STING and type III IFN signaling, with important implications for SARS-CoV-2 infection and antiviral defense. Nature Publishing Group UK 2022-08-06 /pmc/articles/PMC9357023/ /pubmed/35933402 http://dx.doi.org/10.1038/s41419-022-05124-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Karlowitz, Rebekka
Stanifer, Megan L.
Roedig, Jens
Andrieux, Geoffroy
Bojkova, Denisa
Bechtel, Marco
Smith, Sonja
Kowald, Lisa
Schubert, Ralf
Boerries, Melanie
Cinatl, Jindrich
Boulant, Steeve
van Wijk, Sjoerd J. L.
USP22 controls type III interferon signaling and SARS-CoV-2 infection through activation of STING
title USP22 controls type III interferon signaling and SARS-CoV-2 infection through activation of STING
title_full USP22 controls type III interferon signaling and SARS-CoV-2 infection through activation of STING
title_fullStr USP22 controls type III interferon signaling and SARS-CoV-2 infection through activation of STING
title_full_unstemmed USP22 controls type III interferon signaling and SARS-CoV-2 infection through activation of STING
title_short USP22 controls type III interferon signaling and SARS-CoV-2 infection through activation of STING
title_sort usp22 controls type iii interferon signaling and sars-cov-2 infection through activation of sting
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9357023/
https://www.ncbi.nlm.nih.gov/pubmed/35933402
http://dx.doi.org/10.1038/s41419-022-05124-w
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