Apoptosis induced by the toll-like receptor adaptor TRIF is dependent on its receptor interacting protein homotypic interaction motif
Apoptosis induced by the toll-like receptor adaptor TRIF is dependent on its receptor interacting protein homotypic interaction motif
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DOI：
10.4049/jimmunol.174.8.4942
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发表时间：
2005-04-15
影响因子：
4.4
通讯作者：
Offermann, MK
中科院分区：
文献类型：
--
作者：
Kaiser, WJ;Offermann, MK
TLR 检测微生物的特定分子特征，随后通过含 Toll/IL-1R (TIR) 结构域的接头蛋白的不同使用来参与不同的信号网络。在本研究中，我们研究了含 TIR 结构域的接头蛋白 MyD88、含 TIR 结构域的接头蛋白 (TIRAP)、含 TIR 结构域的接头诱导 IFN-β (TRIF)、TRIF 相关接头分子 (TRAM) 以及无菌 a 基序和 β-连环蛋白/犰狳重复序列对细胞凋亡的控制 （SARM）。过度表达后，TRIF 是唯一有效参与哺乳动物细胞死亡信号通路的 TIR 接头。 TRIF 诱导的细胞死亡需要由 Fas/Apo-1 相关 DD 蛋白-caspase-8 轴启动的 caspase 活性，并且不受内在凋亡机制抑制剂的影响。 TRIF 的促凋亡潜力映射到 C 末端区域，发现该区域含有受体相互作用蛋白 (RIP) 同型相互作用基序 (RHIM)。 TRIF 与含有 RHIM 的蛋白质 RIP1 和 RIP3 发生物理相互作用，缺失和突变分析表明 TRIF 中的 RHIM 对于 TRIF 诱导的细胞凋亡至关重要，并有助于 TRIF 诱导的 NF-κ B 激活。诱导细胞凋亡所需的结构域可以激活 NF-kappa B，但不能激活 IFN 调节因子 3，但 NF-kappa B 的激活可以被超阻遏物 IKBa 阻断，但不会阻断细胞凋亡。因此，TRIF 诱导细胞凋亡的能力并不依赖于其激活 IFN 调节因子 3 或 NF-κ B 的能力，而是依赖于完整 RHIM 的存在。 TRIF 充当 TLR3 和 TLR4 的接头，这两个受体分别由 dsRNA 和 LPS 激活。这些分子基序在病毒和细菌感染过程中会遇到，TRIF 参与时发生的细胞凋亡代表了限制感染传播的重要宿主防御。
TLRs detect specific molecular features of microorganisms and subsequently engage distinct signaling networks through the differential use of Toll/IL-1R (TIR)-domain-containing adapter proteins. In this study, we investigated the control of apoptosis by the TIR domain-containing adapter proteins MyD88, TIR-domain containing adapter protein (TIRAP), TIR-domain-containing adapter-inducing IFN-beta (TRIF), TRIF-related adapter molecule (TRAM), and sterile a motifs and beta-catenin/armadiilo repeats (SARM). Upon overexpression, TRIF was the sole TIR-adapter to potently engage mammalian cell death signaling pathways. TRIF-induced cell death required caspase activity initiated by the Fas/Apo-1-associated DD protein-caspase-8 axis and was unaffected by inhibitors of the intrinsic apoptotic machinery. The proapoptotic potential of TRIF mapped to the C-terminal region that was found to harbor a receptor interacting protein (RIP) homotypic interaction motif (RHIM). TRIF physically interacted with the RHIM-containing proteins RIP1 and RIP3, and deletion and mutational analyses revealed that the RHIM in TRIF was essential for TRIF-induced apoptosis and contributed to TRIF-induced NF-kappa B activation. The domain that was required for induction of apoptosis could activate NF-kappa B but not IFN regulatory factor-3, yet the activation of NF-kappa B could be blocked by superrepressor IKBa without blocking apoptosis. Thus, the ability of TRIF to induce apoptosis was not dependent on its ability to activate either IFN regulatory factor-3 or NF-kappa B but was dependent on the presence of an intact RHIM. TRIF serves as an adaptor for both TLR3 and TLR4, receptors that are activated by dsRNA and LPS, respectively. These molecular motifs are encountered during viral and bacterial infection, and the apoptosis that occurs when TRIF is engaged represents an important host defense to limit the spread of infection.