Open AccessCaspase digestion-resistant homozygous keratin 18 mutation protects mouse liver from apoptosis and injury
Author(s) -
Han Na Yoon,
Sung Yeon Yoon,
Jin Hyuck Hong,
Nam Su Ku
Publication year - 2017
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.187492
Subject(s) - biology , keratin , apoptosis , caspase , mutation , liver injury , digestion (alchemy) , caspase 3 , genetics , caspase 8 , microbiology and biotechnology , cancer research , gene , programmed cell death , endocrinology , chemistry , chromatography
Cytoskeletal keratin 18 (K18) undergoes caspase-mediated digestion during apoptosis, which leads to dramatic keratin filament disassembly. We studied the significance of K18 caspase digestion in a mouse model. We generated transgenic mice expressing human K18 caspase digestion-resistant double-mutant, K18-D238/397E, in mouse (m) K18-null background, and compared their response to Fas-mediated injury. Notably, K18-D238/397E;mK18-null mice were significantly more resistant to Fas-induced injury as compared with K18-WT;mK18-null mice (23% vs 57% lethality, respectively; p<0.001). Similar protection from mouse lethality was observed using the microcystin-LR mediated liver injury. The lower apoptosis in K18-D238/397E;mK18-null livers is associated with delayed degradation and thus sustained activation of cell-survival-related protein kinases including stress activated protein kinases and the NF-κB transcription factor up to 6-8 hrs after Fas administration. However, the activation of the kinases and NF-κB in K18-WT-reconstituted livers decreases dramatically by 8 hrs after Fas administration. In addition, D238/397E double-mutation results in prolonged stability of K18 protein in transfected cells and transgenic livers. Therefore, our results show that the caspase digestion-resistant K18 helps maintaining keratin filament organization and delays apoptosis, thereby resulting in protection from liver-injury.