Open AccessJNK signaling prevents biliary cyst formation through a CASPASE-8–dependent function of RIPK1 during aging
Author(s) -
Karl H. Müller,
Hanna Honcharova-Biletska,
Christiane Koppe,
Michèle Egger,
Lap Kwan Chan,
Anne Theres Schneider,
Lena Küsgens,
Friederike Böhm,
Yannick Boege,
Marc E. Healy,
Johannes Schmitt,
Sarah Comtesse,
Mirco Castoldi,
Christian Preisinger,
Marta Szydlowska,
Enrico Focaccia,
Nadine T. Gaisa,
Sven H. Loosen,
Simone Jörs,
Frank Tacke,
Christoph Roderburg,
Verena Keitel,
Johannes G. Bode,
Peter Boor,
Roger J. Davis,
Thomas Longerich,
Fabian Geisler,
Mathias Heikenwälder,
Achim Weber,
Mihael Vucur,
Tom Luedde
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2007194118
Subject(s) - ripk1 , biology , mediator , microbiology and biotechnology , pathogenesis , homeostasis , kinase , cancer research , necroptosis , apoptosis , programmed cell death , immunology , biochemistry
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.