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For example the viral FLIP (vFLIP) encoded by Kaposi\u2019s 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 <jats:italic>vFlip<\/jats:italic> constitutively in hepatocytes (<jats:italic>vFlip<\/jats:italic><jats:sup><jats:italic>AlbCre+<\/jats:italic><\/jats:sup>) were generated. Transgenic expression of <jats:italic>vFlip<\/jats:italic> 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<jats:italic>.<\/jats:italic> 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 <jats:italic>vFlip<\/jats:italic> expression. In summary our data uncovered that transgenic expression of <jats:italic>vFlip<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/s41419-019-2115-y","type":"journal-article","created":{"date-parts":[[2019,11,21]],"date-time":"2019-11-21T11:03:16Z","timestamp":1574334196000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Modulation of the extrinsic cell death signaling pathway by viral Flip induces acute-death mediated liver failure"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7673-9501","authenticated-orcid":false,"given":"Miriam","family":"Bittel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9263-948X","authenticated-orcid":false,"given":"Andreas E.","family":"Kremer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9276-2824","authenticated-orcid":false,"given":"Michael","family":"St\u00fcrzl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Wirtz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iris","family":"Stolzer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus F.","family":"Neurath","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gianna","family":"Ballon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"G\u00fcnther","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,11,21]]},"reference":[{"key":"2115_CR1","doi-asserted-by":"publisher","first-page":"12100","DOI":"10.1128\/JVI.01169-10","volume":"84","author":"G Morissette","year":"2010","unstructured":"Morissette, G. & Flamand, L. 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