Polyglutamine aggregates stimulate ER stress signals and caspase-12 activation
Polyglutamine aggregates stimulate ER stress signals and caspase-12 activation
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DOI：
10.1093/hmg/11.13.1505
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发表时间：
2002-06-15
影响因子：
3.5
通讯作者：
Momoi, T
中科院分区：
文献类型：
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作者：
Kouroku, Y;Fujita, E;Momoi, T
未折叠和错误折叠蛋白的积累会引起内质网 (ER) 应激，刺激未折叠蛋白反应 (UPR) 和 c-Jun N 末端激酶 (JNK) 激活，并激活位于 ER 上的 caspase-12。关于内质网应激和聚谷氨酰胺[poly(Q)]聚集体之间的关系知之甚少。 Poly(Q)(72) 重复序列 [poly(Q)(72)] 诱导 C2C5 细胞中 ER 应激信号的刺激，例如 JNK 激活、Grp78/Bip 上调和 caspase-12 激活。我们制备了针对小鼠 caspase-12 D-318 裂解位点的抗血清（抗 m12D318），结果表明，具有核周聚集体、细胞质内含物和核内含物的 Poly(Q)(72) 刺激 JNK 激活和抗 m12D318 免疫反应性，但具有分散聚集体和小核聚集体的 Poly(Q)(72) 显示出明显较小的影响。分散在细胞质中的聚(Q)(72)和聚(Q)(11)则没有。抗 m12D318 阳性细胞表现出凋亡特征。与抗 m8D387 免疫反应性不同，抗 m12D318 免疫反应性不与聚 (Q) 共聚集。 Ac-IETD-fmk（caspase-8 抑制剂）和 Ac-DEVD-CHO（caspase-3 抑制剂）不会阻止聚 (Q)(72) 聚集体诱导的抗 m12D318 免疫反应性。在表达 Poly(Q)(72) 聚集体的 caspase-8(-/-) 和 caspase-3(-/-) 小鼠胚胎成纤维细胞中检测到抗 m12D318 免疫反应性。因此，Caspase-12 被 Poly(0)72 聚集体通过独立于 Caspase-8 和 Caspase-3 激活的途径激活，并且 Caspase-12 激活与 Poly(Q) 聚集体介导的细胞死亡密切相关。 ER 应激信号的刺激可能与聚 (Q) 扩张相关的神经退行性疾病的发病机制有关。
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(0)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.