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

Krischuns, Tim; Günl, Franziska; Henschel, Lea; Binder, Marco; Willemsen, Joschka; Schloer, Sebastian; Rescher, Ursula; Gerlt, Vanessa; Zimmer, Gert; Nordhoff, Carolin; Ludwig, Stephan; Brunotte, Linda (2018). Phosphorylation of TRIM28 Enhances the Expression of IFN-β and Proinflammatory Cytokines During HPAIV Infection of Human Lung Epithelial Cells. Frontiers in immunology, 9, p. 2229. Frontiers Research Foundation 10.3389/fimmu.2018.02229

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Human infection with highly pathogenic avian influenza viruses (HPAIV) is often associated with severe tissue damage due to hyperinduction of interferons and proinflammatory cytokines. The reasons for this excessive cytokine expression are still incompletely understood, which has hampered the development of efficient immunomodulatory treatment options. The host protein TRIM28 associates to the promoter regions of over 13,000 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 HPAIV of 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > Host-Pathogen Interaction
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Virology and Immunology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Zimmer, Gert

Subjects:

600 Technology > 610 Medicine & health
600 Technology > 630 Agriculture

ISSN:

1664-3224

Publisher:

Frontiers Research Foundation

Language:

English

Submitter:

Achim Braun Parham

Date Deposited:

22 May 2019 15:45

Last Modified:

26 May 2019 02:35

Publisher DOI:

10.3389/fimmu.2018.02229

PubMed ID:

30323812

BORIS DOI:

10.7892/boris.127526

URI:

https://boris.unibe.ch/id/eprint/127526

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