Kuranaga Erina, Kanuka Hirotaka, Tonoki Ayako, Takemoto Kiwamu, Tomioka Takeyasu, Kobayashi Masatomo, Hayashi Shigeo, Miura Masayuki
Department of Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Cell. 2006 Aug 11;126(3):583-96. doi: 10.1016/j.cell.2006.05.048. Epub 2006 Aug 3.
Caspase activation has been extensively studied in the context of apoptosis. However, caspases also control other cellular functions, although the mechanisms regulating caspases in nonapoptotic contexts remain obscure. Drosophila IAP1 (DIAP1) is an endogenous caspase inhibitor that is crucial for regulating cell death during development. Here we describe Drosophila IKK-related kinase (DmIKKvarepsilon) as a regulator of caspase activation in a nonapoptotic context. We show that DmIKKvarepsilon promotes degradation of DIAP1 through direct phosphorylation. Knockdown of DmIKKvarepsilon in the proneural clusters of the wing imaginal disc, in which nonapoptotic caspase activity is required for proper sensory organ precursor (SOP) development, stabilizes endogenous DIAP1 and affects Drosophila SOP development. Our results demonstrate that DmIKKvarepsilon is a determinant of DIAP1 protein levels and that it establishes the threshold of activity required for the execution of nonapoptotic caspase functions.
半胱天冬酶激活已在细胞凋亡的背景下得到广泛研究。然而，半胱天冬酶也控制其他细胞功能，尽管在非凋亡环境中调节半胱天冬酶的机制仍不清楚。果蝇IAP1（DIAP1）是一种内源性半胱天冬酶抑制剂，对发育过程中细胞死亡的调节至关重要。在这里，我们将果蝇IKK相关激酶（DmIKKε）描述为非凋亡环境中半胱天冬酶激活的调节剂。我们表明，DmIKKε通过直接磷酸化促进DIAP1的降解。在翅成虫盘的神经前体细胞簇中敲低DmIKKε，其中适当的感觉器官前体（SOP）发育需要非凋亡半胱天冬酶活性，可稳定内源性DIAP1并影响果蝇SOP发育。我们的结果表明，DmIKKε是DIAP1蛋白水平的决定因素，并且它确定了执行非凋亡半胱天冬酶功能所需的活性阈值。
