Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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SHR Neuro Krebs Kardio Lipid

Stumptner, C; Fuchsbichler, A; Zatloukal, K; Denk, H.
In vitro production of Mallory bodies and intracellular hyaline bodies: the central role of sequestosome 1/p62.
Hepatology. 2007; 46(3): 851-860. [OPEN ACCESS]
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Autor/innen der Med Uni Graz:
Denk Helmut
Stumptner Cornelia
Zatloukal Kurt

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Plum Analytics:
Mallory bodies (MBs) and intracellular hyaline bodies (IHBs) are characteristic hepatocellular inclusions. MBs are hallmarks of steatohepatitis, whereas IHBs have first been detected in hepatocellular carcinoma. MBs and IHBs contain ubiquitin and sequestosome 1/p62 (p62), a stress-inducible adapter protein with affinity to polyubiquitinated proteins. MBs differ from IHBs by their keratin content and morphology. In vitro transfections were undertaken to study under defined conditions MB and IHB formation, their pathogenesis, and relationship. CHO-K1, TIB73, and HeLa cells were transfected with keratin 8, keratin 18, ubiquitin, p62, and p62 lacking the ubiquitin binding domain (p62DeltaUBA) and analyzed by immunofluorescence, immunoelectron microscopy, and immunoblotting. Transfection of p62 complementary deoxyribonucleic acid (cDNA) alone led to cytoplasmic aggregates consisting of filaments mostly arranged in parallel arrays resembling amyloid and type 1 MBs. Transfection of p62 and ubiquitin resulted in globular cytoplasmic aggregates with indistinct fibrillar ultrastructure resembling IHBs. Cotransfection of p62, keratin 8, and ubiquitin was necessary to produce in vitro type 2 MBs-like aggregates consisting of randomly oriented 10- to 15-nm filaments. A similar result was obtained when keratin 8 was replaced by keratin 18. After cotransfection of p62DeltaUBA, keratin 8, and ubiquitin, keratin formed irregular aggregates with electron-dense granular-amorphous ultrastructure (resembling type 3 MBs), whereas p62DeltaUBA remained in diffuse cytoplasmic distribution. CONCLUSION: Our studies show that in vitro development of classical type 2 MBs requires overexpression of keratin 8 (or keratin 18), ubiquitin, and p62 containing the ubiquitin binding domain, whereas IHBs result from overexpression of p62 together with ubiquitin without keratin involvement.
Find related publications in this database (using NLM MeSH Indexing)
Adaptor Proteins, Signal Transducing - analysis
Animals - analysis
Cell Line - analysis
Cricetinae - analysis
Cytoplasm - chemistry
Humans - chemistry
Hyalin - metabolism
Inclusion Bodies - chemistry
Keratin-8 - analysis
Liver Diseases - metabolism
Mice - metabolism
Protein Structure, Tertiary - genetics
Transfection - genetics
Ubiquitin - analysis

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