Targeting TRAF6 E3 ligase activity with a small-molecule inhibitor combats autoimmunity
Targeting TRAF6 E3 ligase activity with a small-molecule inhibitor combats autoimmunity
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DOI：
10.1074/jbc.ra118.002649
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发表时间：
2018-08-24
影响因子：
4.8
通讯作者：
Hadian, Kamyar
中科院分区：
文献类型：
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作者：
Brenke, Jara K.;Popowicz, Grzegorz M.;Hadian, Kamyar
组成性NE-kappa B信号是慢性炎症和自身免疫性疾病的标志。E3连接酶TNF受体相关因子6 （TRAF6）是连接先天免疫、促炎细胞因子和抗原受体到典型nf - κ B通路的关键调节因子。结构分析和点突变揭示了TRAF6与E2偶联酶泛素偶联酶E2N （Ubc13或UBE2N）结合产生lys63连接的泛素链在炎症和免疫信号传播中的重要作用。破坏TRAF6- ubc13结合的基因突变已被证明可以降低TRAF6的活性，从而降低NE-kappa B的活性。然而，到目前为止，还没有小分子调节剂可以抑制TRAF6-Ubc13相互作用，从而抵消NF-kappa B信号传导和相关疾病。在这里，使用高通量小分子筛选方法，我们发现了TRAF6-Ubc13相互作用的抑制剂，可以在体外和细胞中降低TRAF6-Ubc13活性。我们发现这种化合物C25-140在人和小鼠的原代细胞中也能抑制NF-kappa B在各种免疫和炎症信号通路中的激活。重要的是，C25-140在临床前体内小鼠模型中改善了自身免疫性牛皮癣和类风湿性关节炎的炎症和疾病结局。因此，一流的TRAF6- ubc13抑制剂C25-140扩展了研究泛素系统对免疫信号传导影响的工具箱，并强调了TRAF6 E3连接酶活性在牛皮癣和类风湿性关节炎中的重要性。我们认为，通过小分子抑制TRAF6活性代表了一种有希望的靶向自身免疫性和慢性炎症性疾病的新策略。
Constitutive NE-kappa B signaling represents a hallmark of chronic inflammation and autoimmune diseases. The E3 ligase TNF receptor-associated factor 6 (TRAF6) acts as a key regulator bridging innate immunity, pro-inflammatory cytokines, and antigen receptors to the canonical NF-kappa B pathway. Structural analysis and point mutations have unraveled the essential role of TRAF6 binding to the E2-conjugating enzyme ubiquitin-conjugating enzyme E2 N (Ubc13 or UBE2N) to generate Lys63-linked ubiquitin chains for inflammatory and immune signal propagation. Genetic mutations disrupting TRAF6-Ubc13 binding have been shown to reduce TRAF6 activity and, consequently, NE-kappa B activation. However, to date, no small-molecule modulator is available to inhibit the TRAF6-Ubc13 interaction and thereby counteract NF-kappa B signaling and associated diseases. Here, using a high-throughput small-molecule screening approach, we discovered an inhibitor of the TRAF6 -Ubc13 interaction that reduces TRAF6-Ubc13 activity both in vitro and in cells. We found that this compound, C25-140, impedes NF-kappa B activation in various immune and inflammatory signaling pathways also in primary human and murine cells. Importantly, C25-140 ameliorated inflammation and improved disease outcomes of autoimmune psoriasis and rheumatoid arthritis in preclinical in vivo mouse models. Hence, the first-in-class TRAF6-Ubc13 inhibitor C25-140 expands the toolbox for studying the impact of the ubiquitin system on immune signaling and underscores the importance of TRAF6 E3 ligase activity in psoriasis and rheumatoid arthritis. We propose that inhibition of TRAF6 activity by small molecules represents a promising novel strategy for targeting autoimmune and chronic inflammatory diseases.