ArticleJournal of cell science2014
Mutation of caspase-digestion sites in keratin 18 interferes with filament reorganization, and predisposes to hepatocyte necrosis and loss of membrane integrity.
Article in Journal of cell science, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 34 citations in OpenAlex.
- Transglutaminase-mediated cytokeratin modifications implicated in bile-acid-induced hepatocyte death.The FEBS journal · 2026Article
- The immunobiology of SARS-CoV-2 infection and vaccine responses: potential influences of cross-reactive memory responses and aging on efficacy and off-target effects.Frontiers in immunology · 2024Review
- Hepatic Macrophages as Targets for the MSC-Based Cell Therapy in Non-Alcoholic Steatohepatitis.Biomedicines · 2023Review
- Hypoosmosis alters hepatocyte mitochondrial morphology and induces selective release of carbamoyl phosphate synthetase 1.American journal of physiology. Gastrointestinal and liver physiology · 2023Article
- Cytoskeleton and Associated Proteins: Pleiotropic JNK Substrates and Regulators.International journal of molecular sciences · 2021Review
- Revealing the Roles of Keratin 8/18-Associated Signaling Proteins Involved in the Development of Hepatocellular Carcinoma.International journal of molecular sciences · 2021Review
- Danger-Associated Molecular Patterns (DAMPs): Molecular Triggers for Sterile Inflammation in the Liver.International journal of molecular sciences · 2018Review
- The role of keratins in the digestive system: lessons from transgenic mouse models.Histochemistry and cell biology · 2018Review
- Types I and II Keratin Intermediate Filaments.Cold Spring Harbor perspectives in biology · 2018Review
- Article
- Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective Steatohepatitis.Cellular and molecular gastroenterology and hepatology · 2017Article
- Intermediate filament proteins of digestive organs: physiology and pathophysiology.American journal of physiology. Gastrointestinal and liver physiology · 2017Review
- Mouse genetic background contributes to hepatocyte susceptibility to Fas-mediated apoptosis.Molecular biology of the cell · 2016Article
- Keratins: Biomarkers and modulators of apoptotic and necrotic cell death in the liver.Hepatology (Baltimore, Md.) · 2016Review
- Prevalence of genetic variants of keratins 8 and 18 in patients with drug-induced liver injury.BMC medicine · 2015Article
- Carbamoyl phosphate synthetase-1 is a rapid turnover biomarker in mouse and human acute liver injury.American journal of physiology. Gastrointestinal and liver physiology · 2014Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Keratin 18 (K18 or KRT18) undergoes caspase-mediated cleavage during apoptosis, the significance of which is poorly understood. Here, we mutated the two caspase-cleavage sites (D238E and D397E) in K18 (K18-DE), followed by transgenic overexpression of the resulting mutant. We found that K18-DE mice develop extensive Fas-mediated liver damage compared to wild-type mice overexpressing K18 (K18-WT). Fas-stimulation of K18-WT mice or isolated hepatocytes caused K18 degradation. By contrast, K18-DE livers or hepatocytes maintained intact keratins following Fas-stimulation, but showed hypo-phosphorylation at a major stress-kinase-related keratin 8 (K8) phosphorylation site. Although K18-WT and K18-DE hepatocytes showed similar Fas-mediated caspase activation, K18-DE hepatocytes were more 'leaky' after a mild hypoosmotic challenge and were more susceptible to necrosis after Fas-stimulation or severe hypoosmotic stress. K8 hypophosphorylation was not due to the inhibition of kinase binding to the keratin but was due to mutation-induced inaccessibility to the kinase that phosphorylates K8. A stress-modulated keratin phospho-mutant expressed in hepatocytes phenocopied the hepatocyte susceptibility to necrosis but was found to undergo keratin filament reorganization during apoptosis. Therefore, the caspase cleavage of keratins might promote keratin filament reorganization during apoptosis. Interference with keratin caspase cleavage shunts hepatocytes towards necrosis and increases liver injury through the inhibition of keratin phosphorylation. These findings might extend to other intermediate filament proteins that undergo proteolysis during apoptosis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.