Modulation of the extrinsic cell death signaling pathway by viral Flip induces acute-death mediated liver failure

Bittel M, Kremer A, Stürzl M, Wirtz S, Stolzer I, Neurath M, Ballon G, Günther C (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Cell Death & Disease Nature Publishing Group: Open Access Journals - Option B / Nature Publishing Group

Book Volume: 10

Article Number: 878

Journal Issue: 12

DOI: 10.1038/s41419-019-2115-y

Abstract

During viral infections viruses express molecules that interfere with the host-cell death machinery and thus inhibit cell death responses. For example the viral FLIP (vFLIP) encoded by Kaposi’s sarcoma-associated herpesvirus interacts and inhibits the central cell death effector, Caspase-8. In order to analyze the impact of anti-apoptotic viral proteins, like vFlip, on liver physiology in vivo, mice expressing vFlip constitutively in hepatocytes (vFlipAlbCre+) were generated. Transgenic expression of vFlip caused severe liver tissue injury accompanied by massive hepatocellular necrosis and inflammation that finally culminated in early postnatal death of mice. On a molecular level, hepatocellular death was mediated by RIPK1-MLKL necroptosis driven by an autocrine TNF production. The loss of hepatocytes was accompanied by impaired bile acid production and disruption of the bile duct structure with impact on the liver-gut axis. Notably, embryonic development and tissue homeostasis were unaffected by vFlip expression. In summary our data uncovered that transgenic expression of vFlip can cause severe liver injury in mice, culminating in multiple organ insufficiency and death. These results demonstrate that viral cell death regulatory molecules exhibit different facets of activities beyond the inhibition of cell death that may merit more sophisticated in vitro and in vivo analysis.

Authors with CRIS profile

Miriam Bittel Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Andreas Kremer Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Michael Stürzl Professur für Molekulare und Experimentelle Chirurgie Stefan Wirtz Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Iris Stolzer Medizinische Fakultät Markus Neurath Lehrstuhl für Innere Medizin I Claudia Günther Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Involved external institutions

Cooper University Hospital US United States (USA) (US)

How to cite

APA:

Bittel, M., Kremer, A., Stürzl, M., Wirtz, S., Stolzer, I., Neurath, M.,... Günther, C. (2019). Modulation of the extrinsic cell death signaling pathway by viral Flip induces acute-death mediated liver failure. Cell Death & Disease, 10(12). https://doi.org/10.1038/s41419-019-2115-y

MLA:

Bittel, Miriam, et al. "Modulation of the extrinsic cell death signaling pathway by viral Flip induces acute-death mediated liver failure." Cell Death & Disease 10.12 (2019).

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