The E3 ubiquitin ligases HOIP and cIAP1 are recruited to the TNFR2 signaling complex and mediate TNFR2-induced canonical NF-κB signaling
The E3 ubiquitin ligases HOIP and cIAP1 are recruited to the TNFR2 signaling complex and mediate TNFR2-induced canonical NF-κB signaling
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DOI：
10.1016/j.bcp.2018.01.039
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发表时间：
2018-07-01
影响因子：
5.8
通讯作者：
Beyaert, Rudi
中科院分区：
文献类型：
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作者：
Borghi, Alice;Haegman, Mira;Beyaert, Rudi
肿瘤坏死因子（TNF）是一种促炎细胞因子，其通过结合两种细胞表面TNF受体（TNFR）（TNFR 1和TNFR 2）来激发其作用，所述TNFR 1和TNFR 2由许多不同的细胞类型表达。TNFR 1的刺激激活典型的NF-κ B信号传导，导致大量基因的NF-κ B依赖性表达。典型的NF-κ B信号传导需要在细胞膜上组装TNFR 1信号传导复合物，其形成受不同蛋白质泛素化事件调节。在这种情况下，招募线性泛素链组装复合物（LUBAC）TNFR 1通过介导特定NF-κ B信号蛋白的M1连接的多聚泛素化发挥重要作用。与TNFR 1相反，关于泛素化在TNFR 2信号传导中的作用知之甚少。在这里，我们证明，特异性TNFR 2刺激迅速触发M1-和K63-连接的多泛素化的TNFR 2信号复合物。一致的是，TNFR 2刺激诱导HOIP（LUBAC组分和唯一已知的用于M1-聚泛素化的E3泛素连接酶）募集至TNFR 2信号传导复合物。cIAP 1，一种能够用K63-聚泛素链修饰蛋白质的E3泛素连接酶，也被募集到TNFR 2信号传导复合物中。用cIAP拮抗剂处理细胞抑制HOIP的募集，并阻止HOIP介导的TNFR 2信号传导复合物的M1-泛素化，表明HOIP向TNFR 2的募集依赖于cIAP。最后，我们发现HOIP和cIAP 1都是TNFR 2诱导的典型NF-κ B激活所必需的。总之，我们的研究结果证明了M1和K63连接的多聚泛素化在TNFR 2信号传导中的重要作用。
Tumor Necrosis Factor (TNF) is a proinflammatory cytokine that elicits its action by binding to two cell surface TNF receptors (TNFR), TNFR1 and TNFR2, which are expressed by many different cell types. Stimulation of TNFR1 activates canonical NF-kappa B signaling, leading to the NF-kappa B dependent expression of a large number of genes. Canonical NF-kappa B signaling requires the assembly of a TNFR1 signaling complex at the cell membrane, whose formation is regulated by different protein ubiquitination events. In this context, recruitment of the Linear Ubiquitin Chain Assembly Complex (LUBAC) to TNFR1 plays an important role by mediating M1-linked polyubiquitination of specific NF-kappa B signaling proteins. In contrast to TNFR1, much less is known about the role of ubiquitination in TNFR2 signaling. Here we demonstrate that specific TNFR2 stimulation rapidly triggers M1- and K63-linked polyubiquitination at the TNFR2 signaling complex. In agreement, TNFR2 stimulation induces the recruitment of HOIP, a LUBAC component and the only known E3 ubiquitin ligase for M1-polyubiquitination, to the TNFR2 signaling complex. Also cIAP1, a E3 ubiquitin ligase able to modify proteins with K63-polyubiquitin chains, was recruited to the TNFR2 signaling complex. Treatment of cells with a cIAP antagonist inhibited the recruitment of HOIP and prevented HOIP-mediated M1-ubiquitination of the TNFR2 signaling complex, indicating that HOIP recruitment to the TNFR2 relies on cIAPs. Finally, we show that both HOIP and cIAP1 are required for TNFR2-induced canonical NF-kappa B activation. Together, our findings demonstrate an important role for M1- and K63-linked polyubiquitination in TNFR2 signaling.