JNK signaling prevents biliary cyst formation through a CASPASE-8-dependent function of RIPK1 during aging
Document Type
Journal ArticlePublication Date
2021-03-23Keywords
MK2cholangiocytes
liver
liver cysts
programmed cell death
Amino Acids, Peptides, and Proteins
Cell Biology
Cellular and Molecular Physiology
Enzymes and Coenzymes
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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) (JNK1/2(LPC-KO) mice; KO, knockout), we unraveled a function of the JNK pathway in the regulation of liver homeostasis during aging. Aging JNK1/2(LPC-KO) mice spontaneously developed large biliary cysts that originated from the biliary cell compartment. Mechanistically, we could show that cyst formation in livers of JNK1/2(LPC-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.Source
Müller K, Honcharova-Biletska H, Koppe C, Egger M, Chan LK, Schneider AT, Küsgens L, Böhm F, Boege Y, Healy ME, Schmitt J, Comtesse S, Castoldi M, Preisinger C, Szydlowska M, Focaccia E, Gaisa NT, Loosen SH, Jörs S, Tacke F, Roderburg C, Keitel V, Bode JG, Boor P, Davis RJ, Longerich T, Geisler F, Heikenwalder M, Weber A, Vucur M, Luedde T. JNK signaling prevents biliary cyst formation through a CASPASE-8-dependent function of RIPK1 during aging. Proc Natl Acad Sci U S A. 2021 Mar 23;118(12):e2007194118. doi: 10.1073/pnas.2007194118. PMID: 33798093; PMCID: PMC8000530. Link to article on publisher's site
DOI
10.1073/pnas.2007194118Permanent Link to this Item
http://hdl.handle.net/20.500.14038/41857PubMed ID
33798093Notes
Full author list omitted for brevity. For the full list of authors, see article.
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Copyright © 2021 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).Distribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1073/pnas.2007194118
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Except where otherwise noted, this item's license is described as Copyright © 2021 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).