Journal Article

Polyglutamine aggregates stimulate ER stress signals and caspase-12 activation

Yoriko Kouroku, Eriko Fujita, Atsushi Jimbo, Tateki Kikuchi, Takanori Yamagata, Mariko Y. Momoi, Eiki Kominami, Keisuke Kuida, Kazuhiro Sakamaki, Shin Yonehara and Takashi Momoi

in Human Molecular Genetics

Volume 11, issue 13, pages 1505-1515
Published in print June 2002 | ISSN: 0964-6906
Published online June 2002 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/11.13.1505
Polyglutamine aggregates stimulate ER stress signals and caspase-12 activation

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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 D318 (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.

Journal Article.  5932 words.  Illustrated.

Subjects: Genetics and Genomics

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