Polyglutamine aggregates stimulate ER stress signals and caspase-12 activation

Hum Mol Genet. 2002 Jun 15;11(13):1505-15. doi: 10.1093/hmg/11.13.1505.

Abstract

Accumulation of unfolded and malfolded proteins causes endoplasmic reticulum (ER) stress, stimulating unfolded protein response (UPR) and c-Jun N-terminal kinase (JNK) activation and activating caspase-12 located on the ER. Little is known about the relationship between the ER stress and polyglutamine [poly(Q)] aggregates. Poly(Q)72 repeats [poly(Q)(72)] induced the stimulation of ER stress signals such as JNK activation, upregulation of Grp78/Bip and caspase-12 activation in C2C5 cells. We prepared antiserum against the cleavage site of mouse caspase-12 at D(318) (anti-m12D318), and showed that poly(Q)(72) with perinuclear aggregates, cytoplasmic inclusions and nuclear inclusions stimulated JNK activation and anti-m12D318 immunoreactivity, but poly(Q)(72) with dispersed aggregates and small nuclear aggregates showed a significantly less effect. Poly(Q)(72) and poly(Q)(11) dispersed in cytoplasm did not. Anti-m12D318-positive cells showed apoptotic features. Unlike anti-m8D387 immunoreactivity, the anti-m12D318 immunoreactivity was not coaggregated with poly(Q). Ac-IETD-fmk (caspase-8 inhibitor) and Ac-DEVD-CHO (caspase-3 inhibitor) did not prevent the anti-m12D318 immunoreactivity induced by poly(Q)(72) aggregates. Anti-m12D318 immunoreactivity was detected in caspase-8(-/-) and caspase-3(-/-) mouse embryonic fibroblasts expressing poly(Q)(72) aggregates. Thus, caspase-12 was activated by poly(Q)(72) aggregates via a pathway independent of caspase-8 and caspase-3 activation, and caspase-12 activation was closely associated with poly(Q) aggregate-mediated cell death. Stimulation of ER stress signals may be involved in the pathogenesis of neurodegenerative disorders with poly(Q) expansion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • COS Cells
  • Carrier Proteins / metabolism
  • Caspase 12
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism*
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum Chaperone BiP
  • Enzyme Activation
  • Genes, jun
  • Heat-Shock Proteins*
  • Immunoblotting
  • JNK Mitogen-Activated Protein Kinases
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Molecular Chaperones / metabolism
  • Peptides / metabolism*
  • Signal Transduction / physiology

Substances

  • Carrier Proteins
  • Endoplasmic Reticulum Chaperone BiP
  • Heat-Shock Proteins
  • Hspa5 protein, mouse
  • Molecular Chaperones
  • Peptides
  • polyglutamine
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Casp12 protein, mouse
  • Casp8 protein, mouse
  • Casp9 protein, mouse
  • Caspase 12
  • Caspase 8
  • Caspase 9
  • Caspases