Crucial Roles of the RIP Homotypic Interaction Motifs of RIPK3 in RIPK1-Dependent Cell Death and Lymphoproliferative Disease
Crucial Roles of the RIP Homotypic Interaction Motifs of RIPK3 in RIPK1-Dependent Cell Death and Lymphoproliferative Disease
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RIPK3 的 RIP 同型相互作用基序在 RIPK1 依赖性细胞死亡和淋巴增殖性疾病中的关键作用
DOI：
10.1016/j.celrep.2020.107650
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发表时间：
2020
期刊：
影响因子：
8.8
通讯作者：
Zhang Haibing
中科院分区：
文献类型：
--
作者：
Zhang Haiwei;Wu Xiaoxia;Li Xiaoming;Li Ming;Li Fang;Wang Lingxia;Zhang Xixi;Zhang Yue;Luo Yan;Wang Hui;Jiang Yiguo;Zhang Haibing
受体相互作用蛋白激酶3(RIPK3)被认为是坏死性下垂、细胞凋亡和炎症信号的重要调节因子。RIPK3含有一个N-末端的激酶结构域和一个C-末端的RIP同型相互作用基序(Rhim)。然而，RIPK3 Rhim的生理作用仍不清楚。在这里，我们产生了内源性表达RIPK3 Rhim突变体RIPK3V448P的敲门小鼠。表达RIPK3V448P的细胞对RIPK1依赖的细胞凋亡和坏死下垂具有抵抗力，Ripk3V448P/V448P小鼠通过交叉杂交拯救FADD缺陷小鼠的胚胎致死性。与Ripk3−/−FADD−/−小鼠相比，Ripk3V448P/V448PFAdd小鼠表现出更严重的淋巴增生性疾病，异常CD3+B220+淋巴细胞显著增加。更重要的是，Ripk3V448P/V448PFAdd−/−小鼠的这些炎症性疾病被Ripk1的额外缺失深深地抑制了。综上所述，这些结果揭示了RIPK3的RHIM在调节RIPK1依赖的细胞死亡和淋巴增生性疾病方面的先前未知的生理功能。
Receptor-interacting protein kinase 3 (RIPK3) has been identified as an essential regulator of necroptosis, apoptosis, and inflammatory signaling. RIPK3 contains an N-terminal kinase domain and a C-terminal RIP homotypic interaction motif (RHIM). However, the physiological roles of RIPK3 RHIM remain unclear. Here we generate knockin mice endogenously expressing the RIPK3 RHIM mutant, RIPK3V448P. Cells expressing RIPK3V448Pare resistant to RIPK1 kinase-dependent apoptosis and necroptosis, andRipk3V448P/V448Pmice rescue embryonic lethality ofFadd-deficient mice by intercrossing. Strikingly,Ripk3V448P/V448PFadd−/−mice display more severe lymphoproliferative disease with a marked increase in abnormal CD3+B220+lymphocytes compared withRipk3−/−Fadd−/−mice. More importantly, these inflammatory morbidities inRipk3V448P/V448PFadd−/−mice are profoundly inhibited by additional deletion ofRipk1. Taken together, these results reveal a previously unidentified physiological function of RHIM of RIPK3 in regulating RIPK1-dependent cell death and lymphoproliferative disease.