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SHR Neuro Cancer Cardio Lipid Metab Microb

Janig, E; Stumptner, C; Fuchsbichler, A; Denk, H; Zatloukal, K.
Interaction of stress proteins with misfolded keratins.
EUR J CELL BIOL. 2005; 84(2-3): 329-339. Doi: 10.1016/j.ejcb.2004.12.019
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Leading authors Med Uni Graz

Janig Elke

Zatloukal Kurt

Co-authors Med Uni Graz

Denk Helmut

Stumptner Cornelia

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Abstract:

Misfolded and aggregated proteins are a characteristic feature of a variety of chronic diseases. Examples include neurofibrillary tangles in Alzheimer disease, Lewy bodies in Parkinson disease and Mallory bodies (MBs) in chronic liver diseases, particularly alcoholic and non-alcoholic steatohepatitis (ASH and NASH). MB formation is at least in part the result of chronic oxidative cell stress in hepatocytes and can be induced in mice by long-term intoxication with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Proteomic analysis revealed that MBs consist of ubiquitinated keratins and the stress proteins Hsp70, Hsp25, and p62. Furthermore, marked overexpression of clusterin, which shares functional properties with small heat shock proteins, was identified by gene expression profiling of DDC-treated mice livers. To investigate whether clusterin has a function in the stress response to misfolded keratins, we performed transfection studies utilizing expression constructs encoding ubiquitin, p62, Hsp27, clusterin, keratin 8, and keratin 18. Ubiquitin was found in a strong and constant association with keratin aggregates, whereas binding of p62 to keratin was variable. Hsp27 did not colocalize with keratin aggregates under these experimental conditions. In contrast, clusterin associated with misfolded keratin only if its signal peptide was deleted and its secretion inhibited. This suggests that clusterin has ability to bind misfolded proteins, including keratins but its physiological function is restricted to the extracellular space. The extracellular localization of clusterin was underlined by immunohistochemical studies in Alzheimer disease brains, where clusterin was constantly found in association with amyloid plaques; in contrast, cytoplasmic inclusions such as neurofibrillary tangles as well as MBs in ASH were negative. Furthermore, we found clusterin in association with elastic fibers in the extracellular matrix in several chronic liver diseases, including ASH and alpha1-antitrypsin deficiency, implying a possible role of clusterin in liver fibrosis.

Find related publications in this database (using NLM MeSH Indexing)

Alzheimer Disease - metabolism

Animals - metabolism

CHO Cells - metabolism

Clusterin - metabolism

Cricetinae - metabolism

Cricetulus - metabolism

Glycoproteins - metabolism

Heat-Shock Proteins - metabolism

Humans - metabolism

Immunohistochemistry - metabolism

Keratins - metabolism

Liver Diseases, Alcoholic - metabolism

Mice - metabolism

Molecular Chaperones - metabolism

Neoplasm Proteins - metabolism

Protein Folding - metabolism

RNA-Binding Proteins - metabolism

Ubiquitin - metabolism

Find related publications in this database (Keywords)

protein aggregation diseases

alcoholic liver disease

Alzheimer disease

alpha(1)-antitrypsin deficiency

mallory body

keratin

clusterin

ubiquitin

p62

heat shock proteins

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