Hitomi Junichi, Katayama Taiichi, Eguchi Yutaka, Kudo Takashi, Taniguchi Manabu, Koyama Yoshihisa, Manabe Takayuki, Yamagishi Satoru, Bando Yoshio, Imaizumi Kazunori, Tsujimoto Yoshihide, Tohyama Masaya
Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
J Cell Biol. 2004 May 10;165(3):347-56. doi: 10.1083/jcb.200310015. Epub 2004 May 3.
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-beta (Abeta)-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 Abeta, and Abeta-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.
最近的研究表明，阿尔茨海默病或局部缺血中的神经元死亡可能源于内质网（ER）功能障碍。尽管在啮齿动物中，半胱天冬酶-12与内质网应激诱导的凋亡以及淀粉样β蛋白（Aβ）诱导的凋亡有关，但类似机制是否在人类中起作用仍存在争议。我们发现，人类半胱天冬酶-4是包括半胱天冬酶-12在内的半胱天冬酶-1亚家族成员，定位于内质网膜，在用内质网应激诱导试剂处理细胞时会被切割，但用其他凋亡试剂处理时不会。半胱天冬酶-4的切割不受Bcl-2过表达的影响，Bcl-2可阻止线粒体上的信号转导，这表明半胱天冬酶-4主要在内质网应激诱导的凋亡中被激活。此外，小干扰RNA降低半胱天冬酶-4的表达可减少某些细胞系中内质网应激诱导的凋亡，但不会减少其他与内质网应激无关的凋亡。给予Aβ也会切割半胱天冬酶-4，小干扰RNA靶向半胱天冬酶-4可减少Aβ诱导的凋亡。因此，半胱天冬酶-4在人类中可作为内质网应激特异性半胱天冬酶发挥作用，并可能参与阿尔茨海默病的发病机制。
