학술논문
JNK signaling prevents biliary cyst formation through a CASPASE-8--dependent function of RIPK1 during aging
Document Type
Report
Author
Mulier, Katrin; Honcharova-Biletska, Hanna; Koppe, Christiane; Egger, Michele; Chan, Lap Kwan; Schneider, Anne T.; Kusgens, Lena; Bohm, Friederike; Boege, Yannick; Healy, Marc E.; Schmitt, Johannes; Comtesse, Sarah; Castoldi, Mirco; Preisinger, Christian; Szydlowska, Marta; Focaccia, Enrico; Gaisa, Nadine T.; Loosen, Sven H.; Jors, Simone; Tacke, Frank; Roderburg, Christoph; Keitel, Verena; Bode, Johannes G.; Boor, Peter; Davis, Roger J.; Longerich, Thomas; Geisler, Fabian; Heikenwalder, Mathias; Weber, Achim; Vucur, Mihael; Luedde, Tom
Source
Proceedings of the National Academy of Sciences of the United States. March 23, 2021, Vol. 118 Issue 12, p1d, 11 p.
Subject
Language
English
ISSN
0027-8424
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 Jnkl and Jnk2 in liver parenchymal cells (LPCs) (JNK[1/2.sup.LPC-KO] mice; KO, knockout), we unraveled a function of the JNK pathway in the regulation of liver homeostasis during aging. Aging JNK[1/2.sup.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 JNK[1/2.sup.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. cholangiocytes | liver cysts | liver | programmed cell death | MK2