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JNK signaling prevents biliary cyst formation through a CASPASE-8-dependent function of RIPK1 during aging

The c-Jun N-terminal kinase (JNK) signaling pathway mediates adaptation to stress signals and has been associated with cell death, cell proliferation, and malignant transformation in the liver. However, up to now, its function was experimentally studied mainly in young mice. By generating mice with...

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Main Authors: Müller, Katrin (Author) , Honcharova-Biletska, Hanna (Author) , Koppe, Christiane (Author) , Egger, Michèle (Author) , Chan, Lap Kwan (Author) , Schneider, Anne T. (Author) , Küsgens, Lena (Author) , Böhm, Friederike (Author) , Boege, Yannick (Author) , Healy, Marc E. (Author) , Schmitt, Johannes (Author) , Comtesse, Sarah (Author) , Castoldi, Mirco (Author) , Preisinger, Christian (Author) , Szydlowska, Marta (Author) , Focaccia, Enrico (Author) , Gaisa, Nadine T. (Author) , Loosen, Sven H. (Author) , Jörs, Simone (Author) , Tacke, Frank (Author) , Roderburg, Christoph (Author) , Keitel, Verena (Author) , Bode, Johannes G. (Author) , Boor, Peter (Author) , Davis, Roger J. (Author) , Longerich, Thomas (Author) , Geisler, Fabian (Author) , Heikenwälder, Mathias (Author) , Weber, Achim (Author) , Vucur, Mihael (Author) , Luedde, Tom (Author)
Format: Article (Journal)
Language:English
Published: March 8, 2021
In: Proceedings of the National Academy of Sciences of the United States of America
Year: 2021, Volume: 118, Issue: 12, Pages: 1-11
ISSN:1091-6490
DOI:10.1073/pnas.2007194118
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1073/pnas.2007194118
Verlag, lizenzpflichtig, Volltext: https://www.pnas.org/content/118/12/e2007194118
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Author Notes:Katrin Müller, Hanna Honcharova-Biletska, Christiane Koppe, Michèle Egger, Lap Kwan Chan, Anne T. Schneider, Lena Küsgens, Friederike Böhm, Yannick Boege, Marc E. Healy, Johannes Schmitt, Sarah Comtesse, Mirco Castoldi, Christian Preisinger, Marta Szydlowska, Enrico Focaccia, Nadine T. Gaisa, Sven H. Loosen, Simone Jörs, Frank Tacke, Christoph Roderburg, Verena Keitel, Johannes G. Bode, Peter Boor, Roger J. Davis, Thomas Longerich, Fabian Geisler, Mathias Heikenwalder, Achim Weber, Mihael Vucur, and Tom Luedde
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Summary:The c-Jun N-terminal kinase (JNK) signaling pathway mediates adaptation to stress signals and has been associated with cell death, cell proliferation, and malignant transformation in the liver. However, up to now, its function was experimentally studied mainly in young mice. By generating mice with combined conditional ablation of Jnk1 and Jnk2 in liver parenchymal cells (LPCs) (JNK1/2LPC-KO mice; KO, knockout), we unraveled a function of the JNK pathway in the regulation of liver homeostasis during aging. Aging JNK1/2LPC-KO mice spontaneously developed large biliary cysts that originated from the biliary cell compartment. Mechanistically, we could show that cyst formation in livers of JNK1/2LPC-KO mice was dependent on receptor-interacting protein kinase 1 (RIPK1), a known regulator of cell survival, apoptosis, and necroptosis. In line with this, we showed that RIPK1 was overexpressed in the human cyst epithelium of a subset of patients with polycystic liver disease. Collectively, these data reveal a functional interaction between JNK signaling and RIPK1 in age-related progressive cyst development. Thus, they provide a functional linkage between stress adaptation and programmed cell death (PCD) in the maintenance of liver homeostasis during aging.
Item Description:Gesehen am 11.05.2021
Physical Description:Online Resource
ISSN:1091-6490
DOI:10.1073/pnas.2007194118

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