Activation of cell-surface proteases promotes necroptosis, inflammation and cell migration  

作　　者：Zhenyu Cai Anling Zhang Swati Choksi Weihua Li Tao Li Xue-Min Zhang Zheng-Gang Liu 

机构地区：[1]Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA [2]Institute of Basic Medical Sciences, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beo'ing 100850, China

出　　处：《Cell Research》2016年第8期886-900,共15页细胞研究（英文版）

摘　　要：Necroptosis is a programmed, caspase-independent cell death that is morphologically similar to necrosis. TNF-induced necroptosis is mediated by receptor-interacting protein kinases, RIP1 and RIP3, and the mixed lineage kinase domain-like （MLKL）. After being phosphorylated by RIP3, MLKL is translocated to the plasma membrane and mediates necroptosis. However, the execution of necroptosis and its role in inflammation and other cellular responses remain largely elusive. In this study, we report that MLKL-mediated activation of cell-surface proteases of the a disintegrin and metailoprotease （ADAM） family promotes necroptosis, inflammation and cell migration. ADAMs are specifically activated at the early stage of necroptosis when MLKL is phosphorylated and translocated to the cell plasma membrane. Activation of ADAMs induces ectodomain shedding of diverse cell-surface proteins including adhesion molecules, receptors, growth factors and cytokines. Importantly, the shedding of cell-surface proteins disrupts cell adhesion and accelerates necroptosis, while the soluble fragments of the cleaved proteins trigger the inflammatory responses. We also demonstrate that the shedding of E-cadherin ectodomain from necroptotic cells promotes cell migration. Thus, our study provides a novel mechanism of necroptosis-induced inflammation and new insights into the physiological and pathological functions of this unique form of cell death.

关 键 词：MLKL ADAM metalloprotease NECROPTOSIS INFLAMMATION 

分 类 号：Q26[生物学—细胞生物学] Q555.7