Heat stress activates RIPK3 through ZBP1

热应激通过ZBP1激活RIPK3

RIPK1, Toll/interleukin-1 receptor domain containing adapter-inducing interferon-b(TRIF), and ZBP1 are RIP homotypic interaction motif (RHIM)–containing proteins that can interact with and activate RIPK3 (5, 19, 20).

RIPK1，Toll/interleukin-1 受体结构域 - 包含适配器诱导干扰素-b (TRIF)，ZBP1是RIP同源作用基序，含有可与RIPK3相互作用并激活RIPK3的蛋白质

We therefore investigated whether these RIPK3-interacting proteins are required for heat stress induced cell death. Deletion of TRIF, mutation of the kinase domain of RIPK1 (RIPK1D/D), or inhibition of RIPK1 by necrostain-1 did not affect heat stress–induced cell death in BMDMs(Fig. 3A and fig. S6, A and B). 

因此我们研究了这些RIPK3相互作用蛋白是不是热应激诱导细胞死亡所必须的。TRIF的缺失，RIPK1的突变，或者RIPK1的抑制都不能影响热应激诱导骨髓巨噬细胞的死亡。

RIPK1 deficiency did not significantly inhibit heat stress–induced cell death in L929 cells (fig. S6A). By contrast,deletion of ZBP1 abrogated the phosphorylation of RIPK3 and MLKL; the cleavage of casp8, casp3, and GSDME; and cell death after heat stress (Fig. 3, A and B). 

RIPK1的缺乏不能显著抑制热应激诱导的L929细胞死亡。相反，ZBP1的缺失终止了热应激后RIPK3和MLKL的磷酸化，casp8，casp3和GSDME的剪切和细胞死亡

These findings were confirmed in L929 cells (fig. S6, C and D). Restoration of ZBP1 expression restored the capacity of Zbp1-deficient cells to undergo cell death after heat stress (Fig. 3C). Human HT-29, a colon cancer cell line that express RIPK3 and RIPK1 but not ZBP1, also failed to undergo heat stress–induced cell death (Fig.3D).

这些发现在L929细胞中得以证实。ZBP1表达重建恢复了热应激下ZBP1缺失细胞的细胞死亡能力。人类HT29细胞，是表达RIPK3和RIPK1的大肠癌细胞系，但不表达ZBP1，也无法进行热应激诱导的细胞死亡。

Expression of exogenous human ZBP1 rendered HT-29 cells susceptible to heat stress induced cell death (Fig. 3D). Furthermore, heat stress induced the interaction between ZBP1 and RIPK3 (Fig. 3, E and F). These data demonstrate that heat stress activates RIPK3 through ZBP1.

外源性人类ZBP1的表达是HT-29细胞对热应激诱导的细胞死亡敏感。另外，热应激还诱导ZBP1和RIPK3的相互作用。这些数据证实了热应激通过ZBP1激活RIPK3。

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