Keratin 18 overexpression but not phosphorylation or filament organization blocks mouse Mallory body formation

Harada, Masaru; Strnad, Pavel; Resurreccion, Evelyn Z.; Ku, Nam Su; Omary, M. Bishr

doi:10.1002/hep.21471

Cited by 33 publications

(21 citation statements)

References 41 publications

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“…In some cases, "cytoplasmic" (e.g. localized 1 μm or more away from the plasma membrane) IFs are observed in simple epithelia, for example in pacreatic acini [32] and in hepatocytes [33]. On the other hand, we have failed to observe "cytoplasmic" keratin IFs in enterocytes [34] (see also Fig.…”

Section: Location Location Location: Apical Distribution Of Intermementioning

confidence: 64%

Intermediate filaments: A role in epithelial polarity

Oriolo

Wald

Palau

et al. 2007

Experimental Cell Research

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Intermediate filaments have long been considered mechanical components of the cell that provide resistance to deformation stress. Practical experimental problems, including insolubility, lack of good pharmacological antagonists, and the paucity of powerful genetic models, have handicapped the research of other functions. In single-layered epithelial cells, keratin intermediate filaments are cortical, either apically polarized or apico-lateral. This review analyzes phenotypes of genetic manipulations of simple epithelial cell keratins in mice and C. elegans that strongly suggest a role of keratins in apico-basal polarization and membrane traffic. Published evidence that intermediate filaments can act as scaffolds for proteins involved in membrane traffic and signaling is also discussed. Such a scaffolding function would generate a highly polarized compartment within the cytoplasm of simple epithelial cells. While in most cases mechanistic explanations for the keratinnull or overexpression phenotypes are still missing, it is hoped investigators will be encouraged to study these as yet poorly understood functions of intermediate filaments.

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Section: Location Location Location: Apical Distribution Of Intermementioning

confidence: 64%

Intermediate filaments: A role in epithelial polarity

Oriolo

Wald

Palau

et al. 2007

Experimental Cell Research

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“…Animal experiments with modification of keratin 8 and 18 and with keratin 8 and keratin 18 knockout mice revealed the essential role of keratin 8 for MB formation, [25][26][27] although the analysis of in vivo developed MBs disclosed the presence of keratin 18 in addition to keratin 8. 30 We therefore tested the capability of transfected keratin 18 to produce MBs in vitro.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, the final formation of inclusion bodies is a complex process, being the result of evasion of cellular rescue mechanisms against abnormal (unfolded or misfolded) and potentially toxic proteins, and requires additional factors, such as impairment of chaperonedependent processes for refolding and of protein degradation systems. 1,13,18,20,26,27 The role of additional stimuli for MB formation is clearly demonstrated by the results obtained with keratin 18 knockout mice: The "widowed" keratin 8 expressed by these animals is normally rapidly degraded and does not accumulate as inclusions. However, these mice respond much more rapidly than wild-type animals to DDC intoxication by MB formation (Stumptner et al, unpublished observation) and spontaneously develop MB at an older age.…”

Section: Discussionmentioning

confidence: 96%

“…1,9,33 As revealed by numerous experimental studies using the DDC-MB model and keratin 8 or keratin 18 knockout or overexpressing mice, overexpression and increase in the keratin 8 to keratin 18 ratio are key factors for MB formation, but additional stimuli are required to ultimately trigger MB formation. 1,25,26,27 The imbalance in the keratin 8 to keratin 18 ratio may be the result of transcriptional or posttranscriptional events or differences in keratin protein turnover (e.g., inhibitory effect of keratin 8 hyperphosphorylation on keratin degradation; increased keratin 8 stability due to transglutaminase action 26,42 ). Accordingly, one can postulate that MBs are more likely to arise in diseases that result in a keratin 8 Ͼ keratin 18 protein imbalance with accumulation of keratin 8.…”

Section: Discussionmentioning

confidence: 99%

“…Keratin 8 was primarily chosen because we and others have shown that keratin 8 is essential for MB formation in vivo. 1,[25][26][27] Because p62 as well as ubiquitin are present in inclusion bodies associated with a variety of chronic neurodegenerative disorders, such as Alzheimer and Parkinson disease, 3,28 results of this study may be relevant in an even greater context.…”

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confidence: 92%

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In vitro production of Mallory bodies and intracellular hyaline bodies: The central role of sequestosome 1 / p62

et al. 2007

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M allory bodies (MBs) and intracellular hyaline bodies (IHBs) are hepatocellular inclusions that may occur in a diversity of chronic liver disorders. 1,2 They differ in their light and electron microscopic appearance and chemical composition but share sequestosome 1/p62 (p62) as a major component. [1][2][3][4] Whereas MBs contain in addition abnormal keratins, ubiquitin, and heat shock proteins, keratins are lacking in classical IHBs. 1,4 P62 is a multifunctional protein 5,6 with several structural motifs that determine its various functions: the SH2 domain binds the tyrosine kinase p56 lck in a phosphotyrosine-independent manner, an acidic interaction domain associates with the atypical protein kinase C and mediates the role of p62 as adapter in tumor necrosis factor alpha-initiated, interleukin-1-initiated, and nerve growth factor-initiated signal transduction, and a ZZ-type zinc finger binds the receptor interactive protein involved in tumor necrosis factor-induced apoptosis. Moreover, p62 contains a binding site for the tumor necrosis factor receptor-associated factor 6, which is an E3 ubiquitin ligase, two PEST (regions rich in proline, glutamate, serine, and threonine) sequences, and the ubiquitin-association (UBA) domain. [5][6][7] We have recently described the simultaneous occurrence of MBs and IHBs in neoplastic (hepatocellular carcinoma) and non-neoplastic (idiopathic copper toxicosis) hepatocytes, and of "hybrid" inclusions consisting of both Abbreviations: cDNA, complementary deoxyribonucleic acid; DDC,3, Ig, immunoglobulin; IHB, intracellular hyaline body; MB, Mallory body; p62, sequestosome 1/p62; UBA,

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Broad Spectrum of Hepatocyte Inclusions in Humans, Animals, and Experimental Models

Strnad

Nuraldeen

Güldiken

et al. 2013

Comprehensive Physiology

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We focus on hepatic inclusions, which are defined as intracellular aggregates of stainable substances. They represent established hallmarks of their respective human disorders, but unlike aggregates found in neurodegenerative disorders are often not well studied. Hepatic inclusions can be subdivided into primary liver aggregates and aggregates found in multiple tissues. The former ones consist of inclusions found in endoplasmic reticulum storage diseases such as α 1-antitrypsin aggregates or ground-glass hepatocytes, p62-containing (Mallory-Denk bodies and intracellular hyaline bodies) and porphyrin-containing inclusions. p62-containing aggregates are not restricted to the liver but are found in multiple other disorders such as Parkinson or Alzheimer disease. Inclusions such as pale bodies or intracellular hyaline bodies are typical for malignant disorders while others (ground-glass hepatocytes and α1-antitrypsin aggregates) are predominantly seen in non-neoplastic tissues. The inclusions, which are not restricted to the liver, are often due to a systemic viral infection, but also due to disruption of glycogen metabolism or systemic inclusion-forming diseases such as polyglutamine disorders or sarcoidosis. Despite their heterogeneity, inclusions share several pathogenic principles such as an imbalance between protein damage/misfolding on one side and repair/degradation on the other side. This is why hepatic aggregates represent a valuable tool to study the aggregation process in general and to improve our understanding of inclusions found in multiple human disorders.

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Keratin 18 overexpression but not phosphorylation or filament organization blocks mouse Mallory body formation

Cited by 33 publications

References 41 publications

Intermediate filaments: A role in epithelial polarity

Intermediate filaments: A role in epithelial polarity

In vitro production of Mallory bodies and intracellular hyaline bodies: The central role of sequestosome 1 / p62

Broad Spectrum of Hepatocyte Inclusions in Humans, Animals, and Experimental Models

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