From Mallory to Mallory–Denk bodies: What, how and why?

Zatloukal, Kurt; French, Samuel W.; Stumptner, Cornelia; Strnad, Pavel; Harada, Masaru; Toivola, Diana M.; Cadrin, Monique; Omary, M. Bishr

doi:10.1016/j.yexcr.2007.04.024

Cited by 310 publications

(389 citation statements)

References 115 publications

Supporting

Mentioning

369

Contrasting

Unclassified

Order By: Relevance

“…5 In addition, IFs are relatively insoluble proteins that comprise the major constituents of protein inclusions/aggregates that are characteristic of several hepatic, neurodegenerative, and muscular disorders. [5][6][7][8][9] These IF-enriched inclusions consist of misfolded and ubiquitinated proteins together with chaperones and the ubiquitin-binding protein p62. 7,10,11 Mallory-Denk-bodies (MDBs) are hepatocyte-specific aggregates and are among the most common inclusion bodies because of the relative high prevalence of associated liver diseases.…”

mentioning

confidence: 99%

“…7,10,11 Mallory-Denk-bodies (MDBs) are hepatocyte-specific aggregates and are among the most common inclusion bodies because of the relative high prevalence of associated liver diseases. 9 MDBs are characteristic of alcoholic steatohepatitis but are also found in other diseases, including nonalcoholic steatohepatitis, primary biliary cirrhosis, and Wilson disease. 9,12,13 MDBs consist mainly of the IFs keratin 8 and 18 (K8/K18) that have undergone several posttranslational modifications, including hyperphosphorylation and transamidation.…”

mentioning

confidence: 99%

“…9 MDBs are characteristic of alcoholic steatohepatitis but are also found in other diseases, including nonalcoholic steatohepatitis, primary biliary cirrhosis, and Wilson disease. 9,12,13 MDBs consist mainly of the IFs keratin 8 and 18 (K8/K18) that have undergone several posttranslational modifications, including hyperphosphorylation and transamidation. 9,13 MDB formation requires an alteration in the normal equimolar K8:K18 ratio (under basal conditions) to disproportional K8ϾK18 levels that ultimately lead to K8 cross-linking and insolubility.…”

mentioning

confidence: 99%

“…9,12,13 MDBs consist mainly of the IFs keratin 8 and 18 (K8/K18) that have undergone several posttranslational modifications, including hyperphosphorylation and transamidation. 9,13 MDB formation requires an alteration in the normal equimolar K8:K18 ratio (under basal conditions) to disproportional K8ϾK18 levels that ultimately lead to K8 cross-linking and insolubility. 9,13 Our understanding of MDB pathogenesis has been facilitated by mouse models whereby feeding mice the hepatotoxic drugs griseofulvin or 3,5-diethoxycarbonyl-1,4-dihydrocollidin (DDC) for 2 to 5 months leads to MDB formation.…”

mentioning

confidence: 99%

“…9,13 MDB formation requires an alteration in the normal equimolar K8:K18 ratio (under basal conditions) to disproportional K8ϾK18 levels that ultimately lead to K8 cross-linking and insolubility. 9,13 Our understanding of MDB pathogenesis has been facilitated by mouse models whereby feeding mice the hepatotoxic drugs griseofulvin or 3,5-diethoxycarbonyl-1,4-dihydrocollidin (DDC) for 2 to 5 months leads to MDB formation. Similar to the human situation, murine MDB formation is reversible, and MDBs largely disappear after switching the animals to a normal diet for 1 month.…”

mentioning

confidence: 99%

See 4 more Smart Citations

“Toxic memory” via chaperone modification is a potential mechanism for rapid mallory-denk body reinduction

Strnad¹,

Guo²,

So³

et al. 2008

Hepatology

Self Cite

View full text Add to dashboard Cite

The cytoplasmic hepatocyte inclusions, Mallory-Denk bodies (MDBs), are characteristic of several liver disorders, including alcoholic and nonalcoholic steatohepatitis. In mice, MDBs can be induced by long-term feeding with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) for 3 to 4 months or rapidly reformed in DDC-induced then recovered mice by DDC refeeding or exposure to a wide range of toxins for only 5 to 7 days. The molecular basis for such a rapid reinduction of MDBs is unknown. We hypothesized that protein changes retained after DDC priming contribute to the rapid MDB reappearance and associate with MDB formation in general terms. Two-dimensional differential-in-gel-electrophoresis coupled with mass spectrometry were used to characterize protein changes in livers from the various treatment groups. The alterations were assessed by real-time reverse-transcription polymerase chain reaction and confirmed by immunoblotting. DDC treatment led to pronounced charged isoform changes in several chaperone families, including Hsp25, 60, 70, GRP58, GRP75, and GRP78, which lasted at least for 1 month after discontinuation of DDC feeding, whereas changes in other proteins normalized during recovery. DDC feeding also resulted in altered expression of Hsp72, GRP75, and Hsp25 and in functional impairment of Hsp60 and Hsp70 as determined using a protein complex formation and release assay. The priming toward rapid MDB reinduction lasts for at least 3 months after DDC discontinuation, but becomes weaker after prolonged recovery. MDB reinduction parallels the rapid increase in p62 and Hsp25 levels as well as keratin 8 cross-linking that is normally associated with MDB formation. Conclusion: Persistent posttranslational modifications in chaperone proteins, coupled with protein cross-linking and altered chaperone expression and function likely contribute to the "toxic memory" of DDC-primed mice. We hypothesize that similar changes are important contributors to inclusion body formation in several diseases. (HEPATOLOGY 2008;48:931-942.)

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

“Toxic memory” via chaperone modification is a potential mechanism for rapid mallory-denk body reinduction

Strnad¹,

Guo²,

So³

et al. 2008

Hepatology

Self Cite

View full text Add to dashboard Cite

show abstract

p62/SQSTM1—Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer

Taniguchi

Yamachika

et al. 2016

FEBS Letters

View full text Add to dashboard Cite

p62/SQSTM1 is a multifunctional signaling hub and autophagy adaptor with many binding partners, which allow it to activate mTORC1-dependent nutrient sensing, NF-κB-mediated inflammatory responses and the NRF2-activated antioxidant defense. p62 recognizes polyubiquitin chains via its C-terminal domain and binds to LC3 via its LIR motif, thereby promoting the autophagic degradation of ubiquitinated cargos. p62 accumulates in many human liver diseases, including non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), where it is a component of Mallory-Denk bodies and intracellular hyaline bodies. Chronic p62 elevation contributes to HCC development by preventing oncogene-induced senescence and death of cancer-initiating cells and enhancing their proliferation. In this review, we discuss p62-mediated signaling pathways and their roles in liver pathophysiology, especially NASH and HCC.

show abstract

Molecular Genetics of Inherited Disorders of Epidermal Keratins

Sprecher

2009

Encyclopedia of Life Sciences

View full text Add to dashboard Cite

Keratins are a major constituent of the epidermal cell cytoskeleton. Apart from their contribution to cell ability to resist mechanical stress, they have been shown to regulate additional biological processes of importance such as protein synthesis, cell migration and apoptosis. Much of this knowledge has been gained through the study of rare disorders, known as keratinopathies, which are caused by mutations in genes encoding the various epidermal keratins . Recently, novel therapeutic approaches for keratin disorders have been tested successfully, thus raising new hopes for the treatment of this group of inherited skin diseases. Key concepts Keratins are major constituent of epithelial cell cytoskeleton and confer to the cell the ability to resist mechanical stress. Keratins play additional nonstructural role such regulation of cell growth, protein synthesis, cell migration and apoptosis. Keratin disorders manifest with clinical and pathological features that reflect the site of expression of the mutant keratins and the specific function of the keratin domain affected by the causative mutation. Keratin disorders are characterized by genetic heterogeneity, namely a single clinical phenotype can result from mutations in different (but sometimes functionally related) genes (e.g. epidermolysis bullosa caused by mutations in at least five genes). Keratin disorders are characterized by phenotypic heterogeneity, namely mutations in the very same gene can give rise to multiple distinct phenotypes (e.g. mutations in KRT1 can cause at least four distinct diseases). Keratin mutations exert a dominant negative effect; hence current approaches are aimed at eliminating the mutant proteins from the skin. Based on this concept, a first clinical trial in humans has recently been launched to test the effect of a siRNA to treat pachyonychia congenita.

show abstract

From Mallory to Mallory–Denk bodies: What, how and why?

Cited by 310 publications

References 115 publications

“Toxic memory” via chaperone modification is a potential mechanism for rapid mallory-denk body reinduction

“Toxic memory” via chaperone modification is a potential mechanism for rapid mallory-denk body reinduction

p62/SQSTM1—Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer

Molecular Genetics of Inherited Disorders of Epidermal Keratins

Contact Info

Product

Resources

About