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

Han Na Yoon, Sung Yeon Yoon, Jin Hyuck Hong, Nam On Ku

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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 superfamilymember 6 (Fas), anti-FasAb. Notably, K18-D238/ 397E;mK18-null mice were significantly more resistant to anti-FasAbinduced injury as compared with K18-WT;mK18-null mice (23% vs 57% lethality, respectively; P < 0.001). The same applied when the toxin microcystin-LR (MLR) was used to induce liver injury, i.e. lethality of K18-D238/397E;mK18-null mice in response to MLR treatment was reduced compared with the control mouse strain. The lesser rate of 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 h after administration of anti-FasAb. However, activation of the kinases and NF-κB in K18-WT-reconstituted livers decreases dramatically 8 h after anti-FasAb administration. In addition, theD238/397E 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 to maintain keratin filament organization and delays apoptosis, thereby resulting in protection from liver injury.

Original languageEnglish
Pages (from-to)2541-2550
Number of pages10
JournalJournal of cell science
Volume130
Issue number15
DOIs
Publication statusPublished - 2017 Aug 1

All Science Journal Classification (ASJC) codes

  • Cell Biology

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