Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, China.
Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, China.
FEBS J. 2024 Oct;291(20):4473-4488. doi: 10.1111/febs.17222. Epub 2024 Jul 8.
Cullin-based RING ligases (CRLs) comprise the largest family of ubiquitin E3 ligases. CRL activity is tightly regulated by cullin neddylation, which has been associated with various diseases. Although inhibitors of CRLs neddylation have been reported, there is a lack of small molecules that can selectively target individual cullins. Here, we identified a natural product, liquidambaric acid (LDA), with relatively selective inhibition properties against cullin (Cul) 2 neddylation, and found that its target, Tumor Necrosis Factor receptor-associated factor 2 (TRAF2) was required for the activity. TRAF2 associates with the Cul2 neddylation complex and regulates the machinery assembly, especially that of E2 (UBC12) and E3 (RBX1) enzymes. In addition, we demonstrated that by intervention of the associations between TRAF2 and the neddylation machinery, LDA disturbed NEDD8 transfer from E1 to E2, therefore blocking Cul2 neddylation. Taken together, we show that TRAF2 plays a positive role in neddylation cascades, and we have identified a small molecule capable of selective modulation of cullin neddylation.
基于 Cullin 的 RING 连接酶（CRLs）构成了泛素 E3 连接酶家族中最大的家族。CRL 活性受到 Cullin 连接酶 neddylation 的严格调控，该过程与多种疾病有关。尽管已经报道了 CRLs neddylation 的抑制剂，但缺乏能够选择性靶向单个 Cullin 的小分子。在这里，我们鉴定出一种天然产物，液体树脂酸（LDA），对 Cullin（Cul）2 neddylation 具有相对选择性的抑制特性，并发现其靶标，肿瘤坏死因子受体相关因子 2（TRAF2）是活性所必需的。TRAF2 与 Cul2 neddylation 复合物结合并调节机器组件的组装，特别是 E2（UBC12）和 E3（RBX1）酶。此外，我们证明通过干预 TRAF2 与 neddylation 机器之间的关联，LDA 扰乱了从 E1 到 E2 的 NEDD8 转移，从而阻断了 Cul2 neddylation。总之，我们表明 TRAF2 在 neddylation 级联中起积极作用，并且我们已经鉴定出一种能够选择性调节 Cullin neddylation 的小分子。
