NEMO regulates a cell death switch in TNF signaling by inhibiting recruitment of RIPK3 to the cell death-inducing complex II.
NEMO regulates a cell death switch in TNF signaling by inhibiting recruitment of RIPK3 to the cell death-inducing complex II.
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DOI：
10.1038/cddis.2016.245
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发表时间：
2016-08-25
影响因子：
9
通讯作者：
Ursini MV
中科院分区：
文献类型：
--
作者：
Pescatore A;Esposito E;Draber P;Walczak H;Ursini MV
色素失禁症是一种罕见的X连锁疾病，其特征是早期男性死亡和杂合子女性的多种异常。IP由NF-κB必需调节因子（NEMO）突变引起。目前的机制模型表明，NEMO作为介导Iκ B-激酶（IKK）复合物募集至肿瘤坏死因子受体1（TNF-R1）的关键组分发挥作用，从而激活促存活NF-κB反应。然而，最近的研究表明，基因激活和细胞死亡抑制是两个独立的活动NEMO。在这里，我们描述了表达IP相关NEMO-A323 P突变体的细胞完全消除了TNF诱导的NF-κB激活，但保留了部分抗凋亡活性，并表现出对坏死性凋亡死亡的高度敏感性。我们发现，在NEMO缺陷细胞中，强有力的caspase激活伴随着RIPK 3向凋亡介导复合物的募集。相比之下，表达泛素结合突变体NEMO-A323 P的细胞没有将RIPK 3招募到复合物II，这是一种阻止半胱天冬酶激活的事件。因此，NEMO独立于NF-κB活化，本身代表了不同TNF-R1诱导复合物的结构和功能动力学的关键组分。这一过程的改变可能导致不同的细胞结果，因此，也在IP患者与不同NEMO突变的病理影响。
Incontinentia Pigmenti (IP) is a rare X-linked disease characterized by early male lethality and multiple abnormalities in heterozygous females. IP is caused by NF-κB essential modulator (NEMO) mutations. The current mechanistic model suggests that NEMO functions as a crucial component mediating the recruitment of the IκB-kinase (IKK) complex to tumor necrosis factor receptor 1 (TNF-R1), thus allowing activation of the pro-survival NF-κB response. However, recent studies have suggested that gene activation and cell death inhibition are two independent activities of NEMO. Here we describe that cells expressing the IP-associated NEMO-A323P mutant had completely abrogated TNF-induced NF-κB activation, but retained partial antiapoptotic activity and exhibited high sensitivity to death by necroptosis. We found that robust caspase activation in NEMO-deficient cells is concomitant with RIPK3 recruitment to the apoptosis-mediating complex. In contrast, cells expressing the ubiquitin-binding mutant NEMO-A323P did not recruit RIPK3 to complex II, an event that prevented caspase activation. Hence NEMO, independently from NF-κB activation, represents per se a key component in the structural and functional dynamics of the different TNF-R1-induced complexes. Alteration of this process may result in differing cellular outcomes and, consequently, also pathological effects in IP patients with different NEMO mutations.
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影响因子：
16
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
通讯作者：
Kaiser WJ
影响因子：
64.8
作者：
Oberst, Andrew;Dillon, Christopher P.;Weinlich, Ricardo;McCormick, Laura L.;Fitzgerald, Patrick;Pop, Cristina;Hakem, Razq;Salvesen, Guy S.;Green, Douglas R.
通讯作者：
Green, Douglas R.
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
3.5
作者：
Gautheron, Jeremie;Pescatore, Alessandra;Courtois, Gilles
通讯作者：
Courtois, Gilles
影响因子：
64.5
作者：
Micheau, O;Tschopp, J
通讯作者：
Tschopp, J