UMMS Affiliation

Program in Molecular Medicine; Davis Lab

Publication Date


Document Type



Amino Acids, Peptides, and Proteins | Cell Biology | Cellular and Molecular Physiology | Enzymes and Coenzymes


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.


MK2, cholangiocytes, liver, liver cysts, programmed cell death

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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).

DOI of Published Version



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

Journal/Book/Conference Title

Proceedings of the National Academy of Sciences of the United States of America


Full author list omitted for brevity. For the full list of authors, see article.

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Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.