Protein phosphatase inhibition in normal and keratin 8/18 assembly- incompetent mouse strains supports a functional role of keratin intermediate filaments in preserving hepatocyte integrity

Diana M. Toivola, M. Bishr Omary, Nam On Ku, Olli Peltola, Hélène Baribault, John E. Eriksson

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Abstract

The function and regulation of keratin 8 (K8) and 18 (K18), intermediate filament (IF) proteins of the liver, are not fully understood. We employed the liver damage induced by microcystin-LR (MC-LR), a liver-specific inhibitor of type-1 and type-2A protein phosphatases, in normal and in keratin assembly-incompetent mouse strains as a model to elucidate the roles of IF phosphorylation in situ. The mouse strains used were wild-type (wt) mice and mice with abnormal filament assembly, caused by a targeted null mutation of the K8 gene or caused by expression of a point-mutated dominant negative human K18. In vivo 32P-labeled wt mice, subsequently injected with a lethal dose of MC-LR, showed hyperphosphorylation, disassembly, and reorganization of K8/K18, in particular K18, indicating high phosphate turnover on liver keratins in situ. At lethal doses, the keratin assembly- incompetent mice displayed liver lesions faster than wt mice, as indicated histopathologically and by liver-specific plasma enzyme elevations. The histological changes included centrilobular hemorrhage in all mouse strains. The assembly-incompetent mice showed a marked vacuolization of periportal hepatocytes. Indistinguishable MC-LR-induced reorganization of microfilaments was observed in all mice, indicating that this effect on microfilaments is not dependent on the presence of functional K8/K18 networks. At sublethal doses of MC-LR, all animals had the same potential to recover from the liver damage. Our study shows that K8/K18 filament assembly is regulated in vivo by serine phosphorylation. The absence or occurrence of defective K8/K18 filaments render animals more prone to liver damage, which supports the previously suggested roles of keratin IFs in maintenance of structural integrity.

Original languageEnglish
Pages (from-to)116-128
Number of pages13
JournalHepatology
Volume28
Issue number1
DOIs
Publication statusPublished - 1998 Jul 13

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Keratin-8
Keratin-18
Intermediate Filaments
Phosphoprotein Phosphatases
Keratins
Hepatocytes
Liver
Actin Cytoskeleton
Phosphorylation
Intermediate Filament Proteins
Protein Phosphatase 2
Serine
Phosphates
Maintenance

All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

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title = "Protein phosphatase inhibition in normal and keratin 8/18 assembly- incompetent mouse strains supports a functional role of keratin intermediate filaments in preserving hepatocyte integrity",
abstract = "The function and regulation of keratin 8 (K8) and 18 (K18), intermediate filament (IF) proteins of the liver, are not fully understood. We employed the liver damage induced by microcystin-LR (MC-LR), a liver-specific inhibitor of type-1 and type-2A protein phosphatases, in normal and in keratin assembly-incompetent mouse strains as a model to elucidate the roles of IF phosphorylation in situ. The mouse strains used were wild-type (wt) mice and mice with abnormal filament assembly, caused by a targeted null mutation of the K8 gene or caused by expression of a point-mutated dominant negative human K18. In vivo 32P-labeled wt mice, subsequently injected with a lethal dose of MC-LR, showed hyperphosphorylation, disassembly, and reorganization of K8/K18, in particular K18, indicating high phosphate turnover on liver keratins in situ. At lethal doses, the keratin assembly- incompetent mice displayed liver lesions faster than wt mice, as indicated histopathologically and by liver-specific plasma enzyme elevations. The histological changes included centrilobular hemorrhage in all mouse strains. The assembly-incompetent mice showed a marked vacuolization of periportal hepatocytes. Indistinguishable MC-LR-induced reorganization of microfilaments was observed in all mice, indicating that this effect on microfilaments is not dependent on the presence of functional K8/K18 networks. At sublethal doses of MC-LR, all animals had the same potential to recover from the liver damage. Our study shows that K8/K18 filament assembly is regulated in vivo by serine phosphorylation. The absence or occurrence of defective K8/K18 filaments render animals more prone to liver damage, which supports the previously suggested roles of keratin IFs in maintenance of structural integrity.",
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Protein phosphatase inhibition in normal and keratin 8/18 assembly- incompetent mouse strains supports a functional role of keratin intermediate filaments in preserving hepatocyte integrity. / Toivola, Diana M.; Omary, M. Bishr; Ku, Nam On; Peltola, Olli; Baribault, Hélène; Eriksson, John E.

In: Hepatology, Vol. 28, No. 1, 13.07.1998, p. 116-128.

Research output: Contribution to journalArticle

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