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 disassembly of keratin filaments. We studied the significance of K18 caspase digestion in a mouse model and generated transgenic mice expressing the human K18 caspase digestion-resistant double-mutant K18-D238/397E in a mouse (m) K18-null background, and compared their response to injury mediated by administration of antibody against tumor necrosis factor receptor superfamily member 6 (Fas), anti-FasAb. Notably, K18-D238/397E;mK18-null mice were significantly more resistant to anti-FasAb-induced injury as compared with K18-WT;mK18-null mice (23% vs 57% lethality, respectively; <0.