CARD-8 protein, a new CARD family member that regulates caspase-1 activation and apoptosis
CARD-8 protein, a new CARD family member that regulates caspase-1 activation and apoptosis
复制标题
DOI：
10.1074/jbc.m107811200
复制
发表时间：
2002-04-19
影响因子：
4.8
通讯作者：
Alnemri, ES
中科院分区：
文献类型：
--
作者：
Razmara, M;Srinivasula, SM;Alnemri, ES
半胱天冬酶相关募集结构域（CARD）是广泛存在于蛋白质中的蛋白质-蛋白质相互作用模块，其在细胞凋亡、NF κ B活化和细胞因子调节中发挥重要作用。在这项研究中，我们确定了一种新的人类蛋白质，CARD-8，它含有一个C-末端CARD结构域与caspase-1/ICE的CARD结构域高度相似。我们证明CARD-8与caspase-1发生物理相互作用，并在THP-1单核细胞系中负调节caspase-1依赖性IL-1 β的产生。CARD-8还结合ICEBERG和伪ICE，这两种最近鉴定的蛋白质结合半胱天冬酶-1的CARD结构域并负调节其活性。逆转录-PCR分析显示CARD-8主要在单核细胞、胎盘、淋巴结和脾脏中表达。这种表达模式与相同细胞和组织中的半胱天冬酶-1表达一致。还发现CARD-8通过TNF-α刺激和异位表达的RICK负调节NF-κ B活化，表明该蛋白质可以控制细胞存活。与这些结果一致，CARD-8在U937或THP-1细胞中的稳定表达使细胞对分化诱导的凋亡敏感。CARD-8的过表达也可以诱导转染细胞的凋亡。结果表明，CARD-8代表了一种新的信号分子，参与了caspase-1和NF-κ B活化的调节。
Caspase-associated recruitment domains (CARD) are protein-protein interaction modules found extensively in proteins that play important roles in apoptosis, NFkappaB activation, and cytokine regulation. In this study we identified a novel human protein, CARD-8, which contains a C-terminal CARD domain with high similarity to the CARD domain of caspase-1/ICE. We demonstrate that CARD-8 interacts physically with caspase-1 and negatively regulates caspase-1-dependent IL-1beta generation in the THP-1 monocytic cell line. CARD-8 binds also to ICEBERG and pseudo-ICE, two other recently identified proteins, which bind to the CARD domain of caspase-1 and negatively regulate its activity. Reverse transcriptase-PCR analysis revealed that CARD-8 is expressed mainly in monocytes, placenta, lymph nodes, and spleen. This pattern of expression is consistent with caspase-1 expression in the same cells and tissues. CARD-8 was also found to negatively regulate NF-kappaB activation by TNF-alpha stimulation and by ectopically expressed RICK, suggesting that this protein may control cell survival. Consistent with these results, stable expression of CARD-8 in U937 or THP-1 cells sensitizes the cells to differentiation-induced apoptosis. Overexpression of CARD-8 can also induce apoptosis in transfected cells. The results suggest that CARD-8 represents a new signaling molecule involved in the regulation of caspase-1 and NF-kappaB activation.