Tan Yinfei, Dourdin Nathalie, Wu Chao, De Veyra Teresa, Elce John S, Greer Peter A
Division of Cancer Biology and Genetics, Queen's University Cancer Research Institute, Kingston, Ontario, Canada.
J Biol Chem. 2006 Jun 9;281(23):16016-24. doi: 10.1074/jbc.M601299200. Epub 2006 Apr 5.
Ubiquitously expressed mu- and m-calpain proteases are implicated in development and apoptosis. They consist of 80-kDa catalytic subunits encoded by the capn1 and capn2 genes, respectively, and a common 28-kDa regulatory subunit encoded by the capn4 gene. The regulatory subunit is required to maintain the stability and activity of mu- and m-calpains. Accordingly, genetic disruption of capn4 in the mouse eliminated both ubiquitous calpain activities. In embryonic fibroblasts derived from these mice, calpain deficiency correlated with resistance to endoplasmic reticulum (ER) stress-induced apoptosis, and this was directly related to a calpain requirement for activation of both caspase-12 and the ASK1-JNK cascade. This study provides compelling genetic evidence for calpain's role in caspase-12 activation at the ER, and reveals a novel role for the ubiquitous calpains in ER-stress induced apoptosis and JNK activation.
普遍表达的μ-和m-钙蛋白酶与发育和细胞凋亡有关。它们分别由capn1和capn2基因编码的80 kDa催化亚基以及由capn4基因编码的共同的28 kDa调节亚基组成。调节亚基是维持μ-和m-钙蛋白酶稳定性和活性所必需的。因此，小鼠中capn4的基因破坏消除了两种普遍存在的钙蛋白酶活性。在源自这些小鼠的胚胎成纤维细胞中，钙蛋白酶缺乏与对内质网（ER）应激诱导的细胞凋亡的抗性相关，这直接与激活caspase-12和ASK1-JNK级联反应所需的钙蛋白酶有关。这项研究为钙蛋白酶在内质网caspase-12激活中的作用提供了令人信服的遗传学证据，并揭示了普遍存在的钙蛋白酶在内质网应激诱导的细胞凋亡和JNK激活中的新作用。
