Rébé Cédric, Cathelin Séverine, Launay Sophie, Filomenko Rodolphe, Prévotat Laurent, L'Ollivier Coralie, Gyan Emmanuel, Micheau Olivier, Grant Steven, Dubart-Kupperschmitt Anne, Fontenay Michaëla, Solary Eric
Institut National de la Santé et de la Recherche Médicale (INSERM) U517, Dijon, France.
Blood. 2007 Feb 15;109(4):1442-50. doi: 10.1182/blood-2006-03-011585. Epub 2006 Oct 17.
Caspases have demonstrated several nonapoptotic functions including a role in the differentiation of specific cell types. Here, we show that caspase-8 is the upstream enzyme in the proteolytic caspase cascade whose activation is required for the differentiation of peripheral-blood monocytes into macrophages. On macrophage colony-stimulating factor (M-CSF) exposure, caspase-8 associates with the adaptor protein Fas-associated death domain (FADD), the serine/threonine kinase receptor-interacting protein 1 (RIP1) and the long isoform of FLICE-inhibitory protein FLIP. Overexpression of FADD accelerates the differentiation process that does not involve any death receptor. Active caspase-8 cleaves RIP1, which prevents sustained NF-kappaB activation, and activates downstream caspases. Together these data identify a role for caspase-8 in monocytes undergoing macrophagic differentiation, that is, the enzyme activated in an atypical complex down-regulates NF-kappaB activity through RIP1 cleavage.
半胱天冬酶已表现出多种非凋亡功能，包括在特定细胞类型分化中发挥作用。在此，我们表明半胱天冬酶-8是蛋白水解性半胱天冬酶级联反应中的上游酶，其激活是外周血单核细胞分化为巨噬细胞所必需的。在暴露于巨噬细胞集落刺激因子（M-CSF）时，半胱天冬酶-8与衔接蛋白Fas相关死亡结构域（FADD）、丝氨酸/苏氨酸激酶受体相互作用蛋白1（RIP1）以及FLICE抑制蛋白FLIP的长异构体相关联。FADD的过表达加速了不涉及任何死亡受体的分化过程。活性半胱天冬酶-8切割RIP1，这可防止持续的核因子κB激活，并激活下游半胱天冬酶。这些数据共同确定了半胱天冬酶-8在单核细胞向巨噬细胞分化过程中的作用，即该酶在非典型复合物中被激活，通过切割RIP1下调核因子κB活性。
