IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-kappaB as well as cell survival and oncogenesis.
IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-kappaB as well as cell survival and oncogenesis.
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DOI：
10.1038/ncb1789
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发表时间：
2008-11
影响因子：
21.3
通讯作者：
Meier, Pascal
中科院分区：
文献类型：
--
作者：
Gyrd-Hansen, Mads;Darding, Maurice;Miasari, Maria;Santoro, Massimo M.;Zender, Lars;Xue, Wen;Tenev, Tencho;da Fonseca, Paula C. A.;Zvelebil, Marketa;Bujnicki, Janusz M.;Lowe, Scott;Silke, John;Meier, Pascal
泛素与靶蛋白的共价连接影响各种细胞过程，包括DNA修复、NF-κB信号传导和细胞存活。最常见的泛素结合调节模式涉及专门的泛素结合蛋白，其结合泛素化蛋白并将其连接到下游生化过程。揭示泛素信息是如何被识别的是至关重要的，因为异常的泛素介导的信号传导有助于肿瘤的形成。最近的证据表明，细胞凋亡抑制剂（IAP）蛋白在癌症中经常过表达，其表达水平与肿瘤发生、化疗耐药性、疾病进展和患者生存率差有关。在这里，我们已经确定了一个进化上保守的泛素相关（乌巴）结构域的IAP，使他们能够结合到赖氨酸63连接的聚泛素。我们发现乌巴结构域对于cIAP 1的致癌潜力、维持内皮细胞存活和保护细胞免受TNF-α诱导的凋亡是必需的。此外，乌巴结构域是XIAP和cIAP 2-MALT 1激活NF-κB所必需的。我们的数据表明cIAP 2-MALT 1的乌巴结构域通过与多聚泛素化NEMO结合来刺激NF-κB信号传导。值得注意的是，98%的cIAP 2-MALT 1融合蛋白保留了乌巴结构域，这表明遍在蛋白结合有助于cIAP 2-MALT 1在MALT淋巴瘤中的致癌潜力。我们的数据确定IAP作为泛素结合蛋白，有助于泛素介导的细胞存活，NF-κB信号传导和肿瘤发生。
The covalent attachment of ubiquitin to target proteins influences various cellular processes, including DNA repair, NF-κB signalling and cell survival. The most common mode of regulation by ubiquitin-conjugation involves specialized ubiquitin-binding proteins that bind to ubiquitylated proteins and link them to downstream biochemical processes. Unravelling how the ubiquitin-message is recognized is essential because aberrant ubiquitin-mediated signalling contributes to tumour formation. Recent evidence indicates that inhibitor of apoptosis (IAP) proteins are frequently overexpressed in cancer and their expression level is implicated in contributing to tumorigenesis, chemoresistance, disease progression and poor patient-survival. Here, we have identified an evolutionarily conserved ubiquitin-associated (UBA) domain in IAPs, which enables them to bind to Lys 63-linked polyubiquitin. We found that the UBA domain is essential for the oncogenic potential of cIAP1, to maintain endothelial cell survival and to protect cells from TNF-α-induced apoptosis. Moreover, the UBA domain is required for XIAP and cIAP2–MALT1 to activate NF-κB. Our data suggest that the UBA domain of cIAP2–MALT1 stimulates NF-κB signalling by binding to polyubiquitylated NEMO. Significantly, 98% of all cIAP2–MALT1 fusion proteins retain the UBA domain, suggesting that ubiquitin-binding contributes to the oncogenic potential of cIAP2–MALT1 in MALT lymphoma. Our data identify IAPs as ubiquitin-binding proteins that contribute to ubiquitin-mediated cell survival, NF-κB signalling and oncogenesis.
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影响因子：
4.8
作者：
Noels, Heidi;van Loo, Geert;Baens, Mathijs
通讯作者：
Baens, Mathijs
影响因子：
16
作者：
Bertrand, Mathieu J. M.;Milutinovic, Snezana;Barker, Philip A.
通讯作者：
Barker, Philip A.
影响因子：
11.4
作者：
Rodriguez, MS;Desterro, JMP;Hay, RT
通讯作者：
Hay, RT
影响因子：
4.8
作者：
Reffey, SB;Wurthner, JU;Duckett, CS
通讯作者：
Duckett, CS
影响因子：
15.9
作者：
Hu, SM;Du, MQ;Yang, XL
通讯作者：
Yang, XL