Cellular Inhibitors of Apoptosis Are Global Regulators of NF-κB and MAPK Activation by Members of the TNF Family of Receptors
Cellular Inhibitors of Apoptosis Are Global Regulators of NF-κB and MAPK Activation by Members of the TNF Family of Receptors
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DOI：
10.1126/scisignal.2001878
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发表时间：
2012-03-20
影响因子：
7.3
通讯作者：
Vucic, Domagoj
中科院分区：
文献类型：
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作者：
Varfolomeev, Eugene;Goncharov, Tatiana;Vucic, Domagoj
肿瘤坏死因子(TNF)家族成员对免疫系统的发育和正常功能是必不可少的。肿瘤坏死因子受体(TNFR)信号转导是通过组装蛋白信号复合体，以泛素依赖的方式激活核因子-kappaB(NF-kappa B)和丝裂原活化蛋白激酶(MAPK)途径。细胞凋亡抑制蛋白(c-IAP)c-IAP1和c-IAP2是E3泛素连接酶，它们通过与适配蛋白TNFR相关因子2(TRAF2)的结构性结合而被招募到TNFR信号复合体中。我们证明了c-IAP1和c-IAP2是TNFR家族成员规范激活NF-kappa B和MAPK所必需的。C-IAPs是肿瘤坏死因子受体(TNFR)信号转导复合体募集kappaB激酶β抑制因子(ikkβ)、IKK调节亚单位NF-kappa B基本调节剂(NEMO)和RBCK1/Hoil1相互作用蛋白(HOIP)及诱导基因表达所必需的。相反，刺激非规范的NF-kappa B途径的TNFR触发了c-IAPs、TRAF2和TRAF3从胞浆到膜组分的移位，这导致了它们的蛋白酶体和溶酶体降解。最后，我们证实了B细胞激活因子受体3的信号诱导了TRAF3的胞浆耗竭，从而使非规范的核因子-kappaB激活。这些结果将c-IAP蛋白定义为TNFR超家族成员激活NF-kappa B和MAPK信号通路的关键调节因子。
Tumor necrosis factor (TNF) family members are essential for the development and proper functioning of the immune system. TNF receptor (TNFR) signaling is mediated through the assembly of protein signaling complexes that activate the nuclear factor kappa B (NF-kappa B) and mitogen-activated protein kinase (MAPK) pathways in a ubiquitin-dependent manner. The cellular inhibitor of apoptosis (c-IAP) proteins c-IAP1 and c-IAP2 are E3 ubiquitin ligases that are recruited to TNFR signaling complexes through their constitutive association with the adaptor protein TNFR-associated factor 2 (TRAF2). We demonstrated that c-IAP1 and c-IAP2 were required for canonical activation of NF-kappa B and MAPK by members of the TNFR family. c-IAPs were required for the recruitment of inhibitor of kappa B kinase beta (IKK beta), the IKK regulatory subunit NF-kappa B essential modulator (NEMO), and RBCK1/Hoil1-interacting protein (HOIP) to TNFR signaling complexes and the induction of gene expression by TNF family members. In contrast, TNFRs that stimulated the noncanonical NF-kappa B pathway triggered translocation of c-IAPs, TRAF2, and TRAF3 from the cytosol to membrane fractions, which led to their proteasomal and lysosomal degradation. Finally, we established that signaling by B cell-activating factor receptor 3 induced the cytosolic depletion of TRAF3, which enabled noncanonical NF-kappa B activation. These results define c-IAP proteins as critical regulators of the activation of NF-kappa B and MAPK signaling pathways by members of the TNFR superfamily.