School of Life Sciences, Peking University, Beijing 100871, China.
National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
Sci Signal. 2022 May 17;15(734):eabn5881. doi: 10.1126/scisignal.abn5881.
Necroptosis is a form of cell death triggered by stimuli such as the tumor necrosis factor family of cytokines, which induce necrotic cell death through the RIPK1-RIPK3-MLKL pathway. We report here that necroptosis is also activated by extracellular osmotic stresses. Unlike the previously identified inducers of necroptosis, osmotic stress stimulated necroptosis through the direct activation of the kinase activity of RIPK3 by an increase in cytosolic pH mediated by the Na/H exchanger SLC9A1. Knockout, knockdown, or chemical inhibition of SLC9A1 blocked necroptosis induced by osmotic stresses. Moreover, setting intracellular pH at above-physiological values directly activated RIPK3 and necroptosis. The activation of RIPK3 by osmotic stresses did not require its RHIM domain, the protein-interacting domain required for the activation of RIPK3 when cells respond to other previously identified necroptotic stimuli. These results thus delineate a pathway that activates necroptosis in response to osmotic stresses.
细胞坏死是一种由肿瘤坏死因子家族细胞因子等刺激引发的细胞死亡形式，其通过 RIPK1-RIPK3-MLKL 途径诱导坏死性细胞死亡。我们在这里报告，细胞外渗透压应激也会激活细胞坏死。与先前确定的细胞坏死诱导剂不同，渗透压应激通过 Na/H 交换蛋白 SLC9A1 介导的细胞质 pH 增加直接激活 RIPK3 的激酶活性来刺激细胞坏死。敲除、敲低或化学抑制 SLC9A1 可阻断渗透压应激诱导的细胞坏死。此外，将细胞内 pH 值设置在高于生理值可直接激活 RIPK3 和细胞坏死。渗透压应激激活 RIPK3 不依赖其 RHIM 结构域，该结构域是细胞对其他先前确定的细胞坏死刺激物做出反应时激活 RIPK3 所必需的蛋白相互作用结构域。因此，这些结果描绘了一条响应渗透压应激激活细胞坏死的途径。
