Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Mahajan, V; Klingstedt, T; Simon, R; Nilsson, KP; Thueringer, A; Kashofer, K; Haybaeck, J; Denk, H; Abuja, PM; Zatloukal, K.
Cross β-sheet conformation of keratin 8 is a specific feature of Mallory-Denk bodies compared with other hepatocyte inclusions.
Gastroenterology. 2011; 141(3):1080-1090.e1-1080-1090.e7
Doi: 10.1053/j.gastro.2011.05.039
Web of Science
PubMed
FullText
FullText_MUG
- Leading authors Med Uni Graz
- Mahajan Vineet Sudheer
- Zatloukal Kurt
- Co-authors Med Uni Graz
- Abuja Peter Michael
- Denk Helmut
- Haybäck Johannes
- Kashofer Karl
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- Abstract:
- BACKGROUND & AIMS: Mallory-Denk bodies (MDBs) are cytoplasmic protein aggregates in hepatocytes in steato-hepatitis and other liver diseases. We investigated the molecular structure of keratin 8 (K8) and 18 (K18), sequestosome 1/p62, and ubiquitin, which are the major constituents of MDBs, to investigate their formation and role in disease pathogenesis. METHODS: Luminescent conjugated oligothiophenes (LCOs), h-HTAA, and p-FTAA are fluorescent amyloid ligands that specifically bind proteins with cross beta-sheet conformation. We used LCOs to investigate conformational changes in MDBs in situ in human and murine livers as well as in transfection studies. RESULTS: LCO analysis showed cross beta-sheet conformation in human MDBs from patients with alcoholic and nonalcoholic steatohepatitis or hepatocellular carcinoma, but not in intracellular hyaline bodies, alpha(1)-antitrypsin deficiency, or ground-glass inclusions. LCOs bound to MDBs induced by 3,5diethoxycarbonyl-1,4-dihydrocollidine feeding of mice at all developmental stages. CHO-K1 cells transfected with various combinations of SQSTM1/p62, ubi, and Krt8/Krt18 showed that K8 was more likely to have cross beta-sheet conformation than K18, whereas p62 never had cross beta-sheet conformation. The different conformational properties of K8 and K18 were also shown by circular dichroism analysis. CONCLUSIONS: K8 can undergo conformational changes from predominantly alpha-helical to cross beta-sheet, which would allow it to form MDBs. These findings might account for the observation that krt8(-/-) mice do not form MDBs, whereas its excess facilitates MDB formation. LCOs might be used in diagnosis of liver disorders; they can be applied to formalin-fixed, paraffin-embedded tissues to characterize protein aggregates in liver cells.
- Find related publications in this database (using NLM MeSH Indexing)
- Adaptor Proteins, Signal Transducing - chemistry
- Animals -
- CHO Cells -
- Carcinoma, Hepatocellular - metabolism
- Cricetinae -
- Cricetulus -
- Fatty Liver - metabolism
- Heat-Shock Proteins - chemistry
- Hepatocytes - metabolism
- Humans -
- Inclusion Bodies - metabolism
- Keratin-18 - chemistry
- Keratin-8 - chemistry
- Liver Neoplasms - metabolism
- Mice -
- Mice, Knockout -
- Protein Structure, Secondary -
- Transfection -
- Find related publications in this database (Keywords)
- Liver Disease
- Protein Aggregation
- Keratin
- p62
- NASH