TY - JOUR
T1 - JNK signaling prevents biliary cyst formation through a CASPASE-8–dependent function of RIPK1 during aging
AU - Müller, Katrin
AU - Honcharova-Biletska, Hanna
AU - Koppe, Christiane
AU - Egger, Michèle
AU - Chan, Lap Kwan
AU - Schneider, Anne T.
AU - Küsgens, Lena
AU - Böhm, Friederike
AU - Boege, Yannick
AU - Healy, Marc E.
AU - Schmitt, Johannes
AU - Comtesse, Sarah
AU - Castoldi, Mirco
AU - Preisinger, Christian
AU - Szydlowska, Marta
AU - Focaccia, Enrico
AU - Gaisa, Nadine T.
AU - Loosen, Sven H.
AU - Jörs, Simone
AU - Tacke, Frank
AU - Roderburg, Christoph
AU - Keitel, Verena
AU - Bode, Johannes G.
AU - Boor, Peter
AU - Davis, Roger J.
AU - Longerich, Thomas
AU - Geisler, Fabian
AU - Heikenwalder, Mathias
AU - Weber, Achim
AU - Vucur, Mihael
AU - Luedde, Tom
N1 - Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/3/23
Y1 - 2021/3/23
N2 - 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.
AB - 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.
KW - Cholangiocytes | liver cysts | liver | programmed cell death | MK2
UR - http://www.scopus.com/inward/record.url?scp=85102692317&partnerID=8YFLogxK
U2 - 10.1073/pnas.2007194118
DO - 10.1073/pnas.2007194118
M3 - Article
C2 - 33798093
AN - SCOPUS:85102692317
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 12
M1 - e2007194118
ER -