期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 293, 期 31, 页码 11971-11983出版社
ELSEVIER
DOI: 10.1074/jbc.M117.802975
关键词
cell signaling; inflammation; NF- B (NF-B); zebrafish; zinc finger; degeneration; digestive organ
资金
- National Key Basic Research Program of China [2015CB942800]
- National Natural Science Foundation of China [31330051, 31730060, 31371483, 91539201]
- Natural Science Foundation Project of Chongqing [cstc2014jcyjA10062, cstc2014jcyjA10088]
- Fundamental Research Funds for the Central Universities [XDJK2015B011]
- 111 Program [B14037]
Degenerative diseases of organs lead to their impaired function. The cellular and molecular mechanisms underlying organ degeneration are therefore of great research and clinical interest but are currently incompletely characterized. Here, using a forward-genetic screen for genes regulating liver development and function in zebrafish, we identified a cq5 mutant that exhibited a liver-degeneration phenotype at 5 days postfertilization, the developmental stage at which a functional liver develops. Positional cloning revealed that the liver degeneration was caused by a single point mutation in the gene zc3h8 (zinc finger CCCH-type containing 8), changing a highly conserved histidine to glutamine at position 353 of the Zc3h8 protein. The zc3h8 mutation-induced liver degeneration in the mutant was accompanied by reduced proliferation, increased apoptosis, and macrophage phagocytosis of hepatocytes. Transcriptional profile analyses revealed up-regulation and activation of both proinflammatory cytokines and the NF-B signaling pathway in the zc3h8 mutant. Suppression of NF-B signaling activity efficiently rescued the proinflammatory cytokine response, as well as the inflammation-mediated liver degeneration phenotype of the mutant. Of note, the zc3h8 mutation-induced degeneration of several other organs, including the gut and exocrine pancreas, indicating that Zc3h8 is a general repressor of inflammation in zebrafish. Collectively, our findings demonstrate that Zc3h8 maintains organ homeostasis by inhibiting the NF-B-mediated inflammatory response in zebrafish and that Zc3h8 dysfunction causes degeneration of multiple organs, including the liver, gut, and pancreas.
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