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

M. Harada, P. Strnad, D. M. Toivola, M. B. Omary

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1753-1764
Number of pages12
JournalExperimental cell research
Volume314
Issue number8
DOIs
StatePublished - May 1 2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cell Biology

Keywords

  • Intermediate filaments
  • Liver
  • Mallory-Denk bodies

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