Malt1 and cIAP2-Malt1 as effectors of NF-kappaB activation: kissing cousins or distant relatives?
Malt1 and cIAP2-Malt1 as effectors of NF-kappaB activation: kissing cousins or distant relatives?
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DOI：
10.1016/j.cellsig.2009.09.033
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发表时间：
2010-01
影响因子：
4.8
通讯作者：
Schaefer BC
中科院分区：
文献类型：
--
作者：
Kingeter LM;Schaefer BC
Malt 1是一种多结构域胞质信号分子，最初被鉴定为大部分MALT淋巴瘤中复发性易位的靶点。这种易位的产物是一种嵌合蛋白，其中N-末端由凋亡抑制剂cIAP 2贡献，C-末端由Malt 1贡献。早期研究表明，Malt 1是NF-κB抗原受体活化的重要中间体，cIAP 2 N-末端和Malt 1 C-末端的并置导致Malt 1 NF-κB刺激活性的失调。初步实验数据进一步表明，Malt 1和cIAP-Malt 1介导的NF-κB活化的分子机制非常相似。然而，最近对Malt 1和cIAP 2-Malt 1的一些研究表明，这些蛋白质通过多种不同的机制影响NF-κB活化，其中一些机制是不重叠的。目前可用的数据表明了一种修订的模型，其中cIAP 2-Malt 1通过一种同样依赖于cIAP 2和Malt 1贡献的结构域的机制诱导NF-κB活化，这赋予自发的寡聚化活性、多聚遍在蛋白结合、蛋白水解活性以及与TRAF 2和TRAF 6的结合和激活。在几个独立的结合位点。相比之下，新出现的数据表明，野生型Malt 1蛋白独特的NF-κB激活主要通过两个蛋白水解切割机制的控制。首先，Malt 1直接切割并灭活A20，A20是抗原受体至NF-κB途径的负调节因子。其次，Malt 1与caspase-8相互作用，诱导caspase-8裂解c-FLIPL，启动一条有助于激活IκB激酶（IKK）复合物的途径。此外，数据表明，Malt 1在NF-κB的抗原受体活化中发挥更有限和集中的作用，用于增强弱抗原信号并刺激NF-κB依赖性应答的定义子集。因此，cIAP 2-Malt 1对NF-κB的有效激活与Malt 1在调节抗原受体连接下游的特异性NF-κB应答中的更微妙作用形成对比。
Malt1 is a multi-domain cytosolic signaling molecule that was originally identified as the target of recurrent translocations in a large fraction of MALT lymphomas. The product of this translocation is a chimeric protein in which the N-terminus is contributed by the apoptosis inhibitor, cIAP2, and the C-terminus is contributed by Malt1. Early studies suggested that Malt1 is an essential intermediate in antigen receptor activation of NF-κB, and that the juxtaposition of the cIAP2 N-terminus and the Malt1 C-terminus results in deregulation of Malt1 NF-κB stimulatory activity. Initial experimental data further suggested that the molecular mechanisms of Malt1- and cIAP-Malt1-mediated NF-κB activation were quite similar. However, a number of more recent studies of both Malt1 and cIAP2-Malt1 now reveal that these proteins influence NF-κB activation by multiple distinct mechanisms, several of which are non-overlapping. Currently available data suggest a revised model in which cIAP2-Malt1 induces NF-κB activation via a mechanism that depends equally on domains contributed by cIAP2 and Malt1, which confer spontaneous oligomerization activity, polyubiquitin binding, proteolytic activity, and association with and activation of TRAF2 and TRAF6 at several independent binding sites. By contrast, emerging data suggest that the wild-type Malt1 protein uniquely contributes to NF-κB activation primarily through the control of two proteolytic cleavage mechanisms. Firstly, Malt1 directly cleaves and inactivates A20, a negative regulator of the antigen receptor-to-NF-κB pathway. Secondly, Malt1 interacts with caspase-8, inducing caspase-8 cleavage of c-FLIPL, initiating a pathway that contributes to activation of the IκB kinase (IKK) complex. Furthermore, data suggest that Malt1 plays a more limited and focused role in antigen receptor activation of NF-κB, serving to augment weak antigen signals and stimulate a defined subset of NF-κB dependent responses. Thus, the potent activation of NF-κB by cIAP2-Malt1 contrasts with the more subtle role of Malt1 in regulating specific NF-κB responses downstream of antigen receptor ligation.
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