RIP3 induces apoptosis independent of pronecrotic kinase activity.
RIP3 induces apoptosis independent of pronecrotic kinase activity.
复制标题
DOI：
10.1016/j.molcel.2014.10.021
复制
发表时间：
2014-11-20
期刊：
影响因子：
16
通讯作者：
Kaiser WJ
中科院分区：
文献类型：
--
作者：
Mandal P;Berger SB;Pillay S;Moriwaki K;Huang C;Guo H;Lich JD;Finger J;Kasparcova V;Votta B;Ouellette M;King BW;Wisnoski D;Lakdawala AS;DeMartino MP;Casillas LN;Haile PA;Sehon CA;Marquis RW;Upton J;Daley-Bauer LP;Roback L;Ramia N;Dovey CM;Carette JE;Chan FK;Bertin J;Gough PJ;Mocarski ES;Kaiser WJ
受体相互作用蛋白激酶3（RIP 3或RIPK 3）已成为坏死性凋亡的核心参与者和控制炎症性疾病的潜在靶点。在这里，三种选择性小分子化合物显示出抑制RIP 3激酶依赖性坏死性凋亡，尽管它们的治疗价值被令人惊讶的浓度依赖性细胞凋亡诱导所破坏。这些化合物与RIP 3相互作用，通过RIP 1（RIPK 1）的RHIM驱动的募集激活半胱天冬酶8（Casp 8），以组装完全独立于促坏死激酶活性和MLKL的Casp 8-FADD-cFLIP复合物。RIP 3激酶死亡的D161 N突变体诱导独立于化合物的自发凋亡;而D161 G、D143 N和K51 A突变体仅在化合物存在时触发凋亡。因此，RIP 3-K51 A突变小鼠（Rip 3 K51 A/K51 A）是存活的和可生育的，与Rip 3D 161 N/D161 N小鼠的围产期致死率形成鲜明对比。因此，RIP 3通过Ripoptosome样平台保持坏死性凋亡和凋亡的平衡。这项工作突出了一个共同的机制，揭示了RIP 3的治疗或遗传干扰RHIM驱动的细胞凋亡。
Receptor interacting protein kinase 3 (RIP3 or RIPK3) has emerged as a central player in necroptosis and a potential target to control inflammatory disease. Here, three selective small molecule compounds are shown to inhibit RIP3 kinase-dependent necroptosis, although their therapeutic value is undermined by a surprising, concentration-dependent induction of apoptosis. These compounds interact with RIP3 to activate caspase 8 (Casp8) via RHIM-driven recruitment of RIP1 (RIPK1) to assemble a Casp8-FADD-cFLIP complex completely independent of pro-necrotic kinase activities and MLKL. RIP3 kinase-dead D161N mutant induces spontaneous apoptosis independent of compound; whereas, D161G, D143N, and K51A mutants only trigger apoptosis when compound is present. Accordingly, RIP3-K51A mutant mice (Rip3K51A/K51A) are viable and fertile, in stark contrast to the perinatal lethality of Rip3D161N/D161N mice. RIP3 therefore holds both necroptosis and apoptosis in balance through a Ripoptosome-like platform. This work highlights a common mechanism unveiling RHIM-driven apoptosis by therapeutic or genetic perturbation of RIP3.