Bivalent IAP antagonists inhibit TRAF2-bound cIAPs and limit TNF-mediated NF-κB signaling.
Bivalent IAP antagonists inhibit TRAF2-bound cIAPs and limit TNF-mediated NF-κB signaling.
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DOI：
10.1038/cddis.2016.283
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发表时间：
2016-09-29
影响因子：
9
通讯作者：
Condon SM
中科院分区：
文献类型：
--
作者：
Condon SM
哺乳动物IAP是多结构域蛋白，其包含至少一个杆状病毒IAP重复（BIR）结构域和若干IAP，包括两个细胞IAP（cIAP 1和cIAP 2）和X染色体连锁IAP（XIAP），包含三个功能独特的BIR结构域，即BIR 1、BIR 2和BIR 3。早期的报道通过半胱天冬酶与XIAP BIR 3和BIR 2结构域之间的直接相互作用将XIAP鉴定为凋亡抑制剂。从线粒体释放的内源性Smac通过其N-末端四肽（即AVPI）与XIAP结合，其促进活性半胱天冬酶的置换和凋亡过程的进一步传播。许多癌症具有增加的XIAP表达的观察结果导致靶向XIAP的小分子Smac模拟物可能充当用于治疗癌症的促凋亡剂的假设。尽管IAP拮抗剂的开发源自该XIAP/半胱天冬酶假说，但现在认识到IAP BIR结构域通过调节多种蛋白质-蛋白质相互作用介导不同的信号转导途径，并且大多数BIR 3结构域定向的IAP拮抗剂通过在有或没有XIAP参与的情况下拮抗cIAP来诱导癌细胞死亡。cIAP 1和cIAP 2是关键的E3泛素连接酶，其负责TNF受体1（TNFR 1）、NLRP 3-半胱天冬酶-1炎性体处的多种蛋白质的信号诱导的转录后修饰以及B细胞存活和响应性。因此，cIAP在通过外源性配体（TNF、TRAIL）调节细胞-细胞通信、针对入侵病原体的细胞内应答和体液免疫中占据独特的位置。3，8由于IAP拮抗剂治疗导致cIAP 1和cIAP 2不同程度的自身泛素化，随后通过泛素-蛋白酶体系统丢失cIAP，1，9 IAP拮抗剂有可能干扰多种信号传导和调节过程，包括免疫调节、炎症和癌细胞存活。
The mammalian IAPs are multi-domain proteins, which contain at least one Baculovirus IAP Repeat (BIR) domain and several IAPs, including the two cellular IAPs (cIAP1 and cIAP2) and the X chromosome-linked IAP (XIAP), contain three functionally-unique BIR domains, that is, BIR1, BIR2, and BIR3. Early reports identified XIAP as an apoptosis suppressor via the direct interaction between caspases and the XIAP BIR3, and BIR2 domains. Endogenous Smac, released from the mitochondria, binds to XIAP through its N-terminal tetrapeptide, that is, AVPI, which promotes displacement of the active caspases and further propagation of the apoptotic process. The observation that many cancers had increased XIAP expression led to the hypothesis that small-molecule Smac-mimetics targeted against XIAP might act as pro-apoptotic agents for the treatment of cancer. Although development of IAP antagonists derived from this XIAP/caspase hypothesis, it is now recognized that IAP BIR domains mediate diverse signal transduction pathways by modulating a variety of protein-protein interactions, and that the majority of BIR3 domain-directed IAP antagonists induced cancer cell death by antagonizing the cIAPs with or without XIAP involvement. cIAP1 and cIAP2 are critical E3 ubiquitin ligases, which are responsible for the signal-induced post-transcriptional modification of multiple proteins at the TNF Receptor 1 (TNFR1), the NLRP3-caspase-1 inflammasome, and B-cell survival and responsiveness. As such, the cIAPs occupy a unique position for regulating cell-cell communication via exogenous ligands (TNF, TRAIL), intracellular response against invading pathogens, and humoral immunity. 3, 8 As IAP antagonist treatment results in the auto-ubiquitylation of cIAP1, and cIAP2 to various extents, with subsequent loss of the cIAPs via the ubiquitin-proteasome system, 1, 9 IAP antagonists have the potential to interfere with multiple signaling and regulatory processes including immunomodulation, inflammation, and cancer cell survival.
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影响因子：
17.1
作者：
McComb, Scott;Aguade-Gorgorio, Julia;Bornhauser, Beat C.
通讯作者：
Bornhauser, Beat C.
影响因子：
7
作者：
Mitsuuchi Y;Benetatos CA;Deng Y;Haimowitz T;Beck SC;Arnone MR;Kapoor GS;Seipel ME;Chunduru SK;McKinlay MA;Begley CG;Condon SM
通讯作者：
Condon SM
影响因子：
7.3
作者：
Condon, Stephen M.;Mitsuuchi, Yasuhiro;Chunduru, Srinivas K.
通讯作者：
Chunduru, Srinivas K.
DOI：
10.1073/pnas.1502400112
发表时间：
2015-05-05
影响因子：
11.1
作者：
Ebert, Gregor;Allison, Cody;Pellegrini, Marc
通讯作者：
Pellegrini, Marc
影响因子：
5.7
作者：
Benetatos, Christopher A.;Mitsuuchi, Yasuhiro;Chunduru, Srinivas K.
通讯作者：
Chunduru, Srinivas K.