ESCRT-III Acts Downstream of MLKL to Regulate Necroptotic Cell Death and Its Consequences.
ESCRT-III Acts Downstream of MLKL to Regulate Necroptotic Cell Death and Its Consequences.
复制标题
DOI：
10.1016/j.cell.2017.03.020
复制
发表时间：
2017-04-06
期刊：
影响因子：
64.5
通讯作者：
Green DR
中科院分区：
文献类型：
--
作者：
Gong YN;Guy C;Olauson H;Becker JU;Yang M;Fitzgerald P;Linkermann A;Green DR
受体相互作用蛋白激酶-3（RIPK 3）激活混合谱系激酶样（MLKL）导致质膜（PM）破坏和一种形式的调节性坏死，称为坏死性凋亡。在这里，我们表明，在坏死性凋亡，MLKL依赖性钙（Ca++）内流和磷脂酰丝氨酸（PS）暴露于外叶的质膜之前PM的完整性损失。MLKL的活化导致产生破裂的PM“气泡”，其中暴露的PS从原本完整的细胞表面释放。ESCRT-III机制是形成这些气泡所必需的，并且当MLKL激活受限或逆转时，其作用是维持细胞的存活。在坏死性细胞死亡的条件下，ESCRT-III控制质膜完整性的持续时间。由于ESCRT-III的作用，经历坏死性凋亡的细胞可以表达趋化因子和其他调节分子，并促进CD 8 + T细胞的抗原交叉引发。
The activation of Mixed Lineage Kinase-Like (MLKL) by Receptor Interacting Protein Kinase-3 (RIPK3) results in plasma membrane (PM) disruption and a form of regulated necrosis, called necroptosis. Here we show that during necroptosis, MLKL-dependent calcium (Ca++) influx and phosphatidylserine (PS) exposure on the outer leaflet of the plasma membrane preceded loss of PM integrity. Activation of MLKL results in the generation of broken, PM “bubbles” with exposed PS that are released from the surface of the otherwise intact cell. The ESCRT-III machinery is required for formation of these bubbles, and acts to sustain survival of the cell when MLKL activation is limited or reversed. Under conditions of necroptotic cell death, ESCRT-III controls the duration of plasma membrane integrity. As a consequence of the action of ESCRT-III, cells undergoing necroptosis can express chemokines and other regulatory molecules, and promote antigenic cross-priming of CD8+ T cells.