Csomos Rebecca A, Wright Casey W, Galbán Stefanie, Oetjen Karolyn A, Duckett Colin S
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Biochem J. 2009 Apr 28;420(1):83-91. doi: 10.1042/BJ20082140.
c-IAP1 (cellular inhibitor of apoptosis 1) has recently emerged as a negative regulator of the non-canonical NF-kappaB (nuclear factor kappaB) signalling cascade. Whereas synthetic IAP inhibitors have been shown to trigger the autoubiquitination and degradation of c-IAP1, less is known about the physiological mechanisms by which c-IAP1 stability is regulated. In the present paper, we describe two distinct cellular processes that lead to the targeted loss of c-IAP1. Recruitment of a TRAF2 (tumour necrosis factor receptor-associated factor 2)-c-IAP1 complex to the cytoplasmic domain of the Hodgkin's/anaplastic large-cell lymphoma-associated receptor, CD30, leads to the targeting and degradation of the TRAF2-c-IAP1 heterodimer through a mechanism requiring the RING (really interesting new gene) domain of TRAF2, but not c-IAP1. In contrast, the induced autoubiquitination of c-IAP1 by IAP antagonists causes the selective loss of c-IAP1, but not TRAF2, thereby releasing TRAF2. Thus c-IAP1 can be targeted for degradation by two distinct processes, revealing the critical importance of this molecule as a regulator of numerous intracellular signalling cascades.
细胞凋亡抑制蛋白1（c-IAP1）最近已成为非经典核因子κB（NF-κB）信号级联反应的负调节因子。虽然合成IAP抑制剂已被证明可触发c-IAP1的自身泛素化和降解，但关于调节c-IAP1稳定性的生理机制却知之甚少。在本文中，我们描述了导致c-IAP1靶向性缺失的两个不同细胞过程。将肿瘤坏死因子受体相关因子2（TRAF2）-c-IAP1复合物招募至霍奇金氏/间变性大细胞淋巴瘤相关受体CD30的胞质结构域，会通过一种需要TRAF2的RING（真有趣的新基因）结构域而非c-IAP1的机制，导致TRAF2-c-IAP1异二聚体的靶向性降解。相比之下，IAP拮抗剂诱导的c-IAP1自身泛素化会导致c-IAP1的选择性缺失，而非TRAF2的缺失，从而释放TRAF2。因此，c-IAP1可通过两个不同过程被靶向降解，这揭示了该分子作为众多细胞内信号级联反应调节因子的关键重要性。
