Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death.
Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death.
复制标题
DOI：
10.1083/jcb.200310015
复制
发表时间：
2004-05-10
影响因子：
7.8
通讯作者：
Tohyama, Masaya
中科院分区：
文献类型：
--
作者：
Hitomi, Junichi;Katayama, Taiichi;Eguchi, Yutaka;Kudo, Takashi;Taniguchi, Manabu;Koyama, Yoshihisa;Manabe, Takayuki;Yamagishi, Satoru;Bando, Yoshio;Imaizumi, Kazunori;Tsujimoto, Yoshihide;Tohyama, Masaya
最近的研究表明，阿尔茨海默病的神经元死亡或缺血可能是由内质网功能障碍引起的。尽管caspase-12与啮齿动物内质网应激诱导的细胞凋亡和淀粉样蛋白-β (Aβ)诱导的细胞凋亡有关，但类似的机制是否在人类中起作用仍存在争议。我们发现人类caspase-4是caspase-1亚家族的一员，包括caspase-12，它定位于内质网膜，当细胞被内质网应激诱导试剂处理时，它被切割，而不是被其他凋亡试剂处理。caspase-4的切割不受Bcl-2过表达的影响，而Bcl-2过表达会阻止线粒体的信号转导，这表明caspase-4主要在内质网应激诱导的细胞凋亡中被激活。此外，通过小干扰RNA降低caspase-4的表达可以减少一些细胞系内质网应激诱导的细胞凋亡，但对其他内质网应激无关的细胞凋亡没有影响。Caspase-4也可被Aβ切割，Aβ诱导的凋亡可通过干扰Caspase-4的小rna减少。因此，caspase-4可以作为人类内质网应激特异性caspase发挥作用，并可能参与阿尔茨海默病的发病机制。
Recent studies have suggested that neuronal death in Alzheimer's disease or ischemia could arise from dysfunction of the endoplasmic reticulum (ER). Although caspase-12 has been implicated in ER stress-induced apoptosis and amyloid-β (Aβ)–induced apoptosis in rodents, it is controversial whether similar mechanisms operate in humans. We found that human caspase-4, a member of caspase-1 subfamily that includes caspase-12, is localized to the ER membrane, and is cleaved when cells are treated with ER stress-inducing reagents, but not with other apoptotic reagents. Cleavage of caspase-4 is not affected by overexpression of Bcl-2, which prevents signal transduction on the mitochondria, suggesting that caspase-4 is primarily activated in ER stress-induced apoptosis. Furthermore, a reduction of caspase-4 expression by small interfering RNA decreases ER stress-induced apoptosis in some cell lines, but not other ER stress-independent apoptosis. Caspase-4 is also cleaved by administration of Aβ, and Aβ-induced apoptosis is reduced by small interfering RNAs to caspase-4. Thus, caspase-4 can function as an ER stress-specific caspase in humans, and may be involved in pathogenesis of Alzheimer's disease.