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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 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.

Titel: Phosphorylation of TRIM28 Enhances the Expression of IFN-beta and Proinflammatory Cytokines During HPAIV Infection of Human Lung Epithelial Cells
Verfasser: Krischuns, Tim
Günl, Franziska
Henschel, Lea
Binder, Marco GND
Willemsen, Joschka GND
Schloer, Sebastian
Rescher, Ursula
Gerlt, Vanessa
Zimmer, Gert GND
Nordhoff, Carolin GND
Ludwig, Stephan
Brunotte, Linda GND
Organisation: FB 13: Biologie
Dokumenttyp: Artikel
Medientyp: Text
Erscheinungsdatum: 28.09.2018
Publikation in MIAMI: 15.10.2018
Datum der letzten Änderung: 15.10.2018
Quelle: Frontiers in Immunology 9 (2018) 2229, 1-16
Schlagwörter: influenza; TRIM28; KAP1; TIF1-beta; IFN-beta; RIG-I; PKR; innate immunity
Fachgebiete: Medizin und Gesundheit
Lizenz: CC BY 4.0
Sprache: Englisch
Format: PDF-Dokument
URN: urn:nbn:de:hbz:6-27119436748
Permalink: https://nbn-resolving.org/urn:nbn:de:hbz:6-27119436748
DOI: 10.3389/fimmu.2018.02229
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