Phosphorylation of TRIM28 Enhances the Expression of IFN-beta and Proinflammatory Cytokines During HPAIV Infection of Human Lung Epithelial Cells

Human infection with highly pathogenic avian influenza viruses (HPAIV) is associated with severe tissue damage due to hyperinduction of interferons and proinflammatory cytokines. The reasons for this excessive cytokine expression are still incompletely understood. The host protein TRIM28 associates...

Authors: Krischuns, Tim
Günl, Franziska
Henschel, Lea
Binder, Marco
Willemsen, Joschka
Schloer, Sebastian Maximilian
Rescher, Ursula
Gerlt, Vanessa
Zimmer, Gert
Nordhoff, Carolin
Ludwig, Stephan
Brunotte, Linda
Division/Institute:FB 13: Biologie
Document types:Article
Media types:Text
Publication date:2018
Date of publication on miami:15.10.2018
Modification date:02.10.2019
Edition statement:[Electronic ed.]
Source:Frontiers in Immunology 9 (2018) 2229, 1-16
Subjects:influenza; TRIM28; KAP1; TIF1-beta; IFN-beta; RIG-I; PKR; innate immunity
DDC Subject:610: Medizin und Gesundheit
License:CC BY 4.0
Language:English
Funding:Finanziert durch den Open-Access-Publikationsfonds 2018 der Deutschen Forschungsgemeinschaft (DFG) und der Westfälischen Wilhelms-Universität Münster (WWU Münster).
Format:PDF document
URN:urn:nbn:de:hbz:6-27119436748
Permalink:http://nbn-resolving.de/urn:nbn:de:hbz:6-27119436748
Other Identifiers:DOI: 10.3389/fimmu.2018.02229
Digital documents:01_artikel_brunotte_2018.pdf
02_zusatzmateriel_brunotte_2018.pdf
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Human infection with highly pathogenic avian influenza viruses (HPAIV) is associated with severe tissue damage due to hyperinduction of interferons and proinflammatory cytokines. The reasons for this excessive cytokine expression are still incompletely understood. The host protein TRIM28 associates to the promoter regions of over 13000 genes and is recognized as a genomic corepressor and negative immune regulator. TRIM28 corepressor activity is regulated by post-translational modifications, specifically phosphorylation of S473, which modulates binding of TRIM28 to the heterochromatin-binding protein HP1. Here, we identified TRIM28 as a key immune regulator leading to increased IFN-β and proinflammatory cytokine levels during infection with HPAIV. Using influenza A virus strains of the subtype H1N1 as well as the HPAIV subtypes H7N7, H7N9 and H5N1, we could demonstrate that strain-specific phosphorylation of TRIM28 S473 is induced by a signaling cascade constituted of PKR, p38 MAPK and MSK1 in response to RIG-I independent sensing of viral RNA. Furthermore, using chemical inhibitors as well as knockout cell lines, our results suggest that phosphorylation of S473 facilitates a functional switch leading to increased levels of IFN-β, IL-6 and IL-8. In summary, we have identified TRIM28 as a critical factor controlling excessive expression of type I IFNs as well as proinflammatory cytokines during infection with H5N1, H7N7 and H7N9 HPAIV. In addition, our data indicate a novel mechanism of PKR-mediated IFN-β expression, which could lay the ground for novel treatment options aiming at rebalancing dysregulated immune responses during severe HPAIV infection.