Autophagy modulates keratin-containing inclusion formation and apoptosis in cell culture in a context-dependent fashion

M Harada, P Strnad, Diana Toivola, MB Omary

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

28 Citeringar (Scopus)

Sammanfattning

The major pathways for protein degradation are the proteasomal and lysosomal systems. Derangement of protein degradation causes the formation of intracellular inclusions, and apoptosis and is associated with several diseases. We utilized hepatocyte-derived cell lines to examine the consequences of the cytoplasmic hepatocyte Mallory-Denk body-like inclusions on organelle organization, autophagy and apoptosis, and tested the hypothesis that autophagy affects inclusion turnover. Proteasome inhibitors (PIs) generate keratin-containing Mallory-Denk body-like inclusions in cultured cells and cause reorganization of mitochondria and other organelles, autophagy and apoptosis. In cultured hepatoma cells, caspase inhibition blocks PI-induced apoptosis but not inclusion formation or autophagy activation. Autophagy induction by rapamycin decreases the extent of PI-induced inclusions and apoptosis in Huh7 and OUMS29 cells. Surprisingly, blocking of autophagy sequestration by 3 methyl adenine or beclin 1 siRNA, but not bafilomycin A1 inhibition of autophagic degradation, also inhibits inclusion formation in the tested cells. Therefore, autophagy can be upstream of apoptosis and may promote or alleviate inclusion formation in cell culture in a context-dependent manner via putative autophagy-associated molecular triggers. Manipulation of autophagy may offer a strategy to address the importance of inclusion formation and its significance in inclusion-associated diseases. Published by Elsevier Inc.
OriginalspråkOdefinierat/okänt
Sidor (från-till)1753–1764
Antal sidor12
TidskriftExperimental Cell Research
Volym314
Utgåva8
DOI
StatusPublicerad - 2008
MoE-publikationstypA1 Tidskriftsartikel-refererad

Nyckelord

  • Mallory-Denk bodies
  • intermediate filaments

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