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Molecular determinants of Smac mimetic induced degradation of cIAP1 and cIAP2

机译:Smac模拟物诱导的cIAP1和cIAP2降解的分子决定因素

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摘要

The inhibitors of apoptosis (IAP) proteins cIAP1 and cIAP2 have recently emerged as key ubiquitin-E3 ligases regulating innate immunity and cell survival. Much of our knowledge of these IAPs stems from studies using pharmacological inhibitors of IAPs, dubbed Smac mimetics (SMs). Although SMs stimulate auto-ubiquitylation and degradation of cIAPs, little is known about the molecular determinants through which SMs activate the E3 activities of cIAPs. In this study, we find that SM-induced rapid degradation of cIAPs requires binding to tumour necrosis factor (TNF) receptor-associated factor 2 (TRAF2). Moreover, our data reveal an unexpected difference between cIAP1 and cIAP2. Although SM-induced degradation of cIAP1 does not require cIAP2, degradation of cIAP2 critically depends on the presence of cIAP1. In addition, degradation of cIAP2 also requires the ability of the cIAP2 RING finger to dimerise and to bind to E2s. This has important implications because SM-mediated degradation of cIAP1 causes non-canonical activation of NF-κB, which results in the induction of cIAP2 gene expression. In the absence of cIAP1, de novo synthesised cIAP2 is resistant to the SM and suppresses TNFα killing. Furthermore, the cIAP2-MALT1 oncogene, which lacks cIAP2's RING, is resistant to SM treatment. The identification of mechanisms through which cancer cells resist SM treatment will help to improve combination therapies aimed at enhancing treatment response.
机译:凋亡(IAP)蛋白cIAP1和cIAP2的抑制剂最近已成为调节先天免疫和细胞存活的关键泛素E3连接酶。我们对这些IAP的很多了解都来自使用IAP的药理抑制剂(称为Smac模拟物(SMs))进行的研究。尽管SM刺激cIAP的自身泛素化和降解,但对于SM激活cIAP的E3活性的分子决定因素知之甚少。在这项研究中,我们发现SM诱导的cIAP的快速降解需要与肿瘤坏死因子(TNF)受体相关因子2(TRAF2)结合。此外,我们的数据揭示了cIAP1和cIAP2之间的意外差异。尽管SM诱导的cIAP1降解不需要cIAP2,但是cIAP2的降解关键取决于cIAP1的存在。另外,cIAP2的降解还需要cIAP2 RING指具有二聚作用并与E2s结合的能力。这具有重要意义,因为SM介导的cIAP1降解会导致NF-κB的非规范激活,从而导致cIAP2基因表达的诱导。在不存在cIAP1的情况下,从头合成的cIAP2对SM具有抗性并抑制TNFα的杀伤。此外,缺少cIAP2的RING的cIAP2-MALT1癌基因对SM治疗有抗性。癌细胞抵抗SM治疗的机制的鉴定将有助于改善旨在增强治疗反应的联合疗法。

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