UMMS Affiliation
Program in Molecular Medicine; Davis Lab
Publication Date
2021-03-23
Document Type
Article
Disciplines
Amino Acids, Peptides, and Proteins | Cell Biology | Cellular and Molecular Physiology | Enzymes and Coenzymes
Abstract
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.
Keywords
MK2, cholangiocytes, liver, liver cysts, programmed cell death
Rights and Permissions
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
10.1073/pnas.2007194118
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
Journal/Book/Conference Title
Proceedings of the National Academy of Sciences of the United States of America
Related Resources
PubMed ID
33798093
Repository Citation
Muller K, Davis RJ, Weber A, Luedde T. (2021). JNK signaling prevents biliary cyst formation through a CASPASE-8-dependent function of RIPK1 during aging. Open Access Publications by UMMS Authors. https://doi.org/10.1073/pnas.2007194118. Retrieved from https://escholarship.umassmed.edu/oapubs/4661
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Included in
Amino Acids, Peptides, and Proteins Commons, Cell Biology Commons, Cellular and Molecular Physiology Commons, Enzymes and Coenzymes Commons
Comments
Full author list omitted for brevity. For the full list of authors, see article.