A mutation in keratin 18 that causes caspase-digestion resistance protects homozygous transgenic mice from hepatic apoptosis and injury

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.