IAP家族蛋白Livin在细胞凋亡中的作用机制研究
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摘要
细胞凋亡(也叫程序性细胞死亡)，是一种由基因控制的主动性的细胞死亡过程，它对于维持机体内环境的稳定是至关重要的。Livin(又称ML-IAP和KIAP)是凋亡抑制蛋白(inhibitor of apoptosis proteins，IAP)家族的一个成员，它含有一个IAP家族特征性的杆状病毒IAP重复序列(baculoviral IAP repeat，BIR)结构域和羧基端的环状锌指样结构区域(RING zinc-finger domain)。已有报道指出，Livin可以通过其BIR结构域在体外直接与caspase-3和—7结合、在体内与caspase-9结合及与促凋亡因子Smac／DIABLO相互作用。且Livin是个相对弱的caspases抑制子，关于这个分子的更为详细的抗凋亡的机制需要进一步的研究和阐明，为此，我们进行了下面的研究并得出了一些结论。
在本研究中，我们首次证实了Livin可以充当E3泛素连接酶并可以泛素化降解Smac／DIABLO。体内和体外的实验证明，Livin的BIR结构域和RING区域对于Livin泛素化降解Smac／DIABLO是必不可缺少的。
我们也发现，Livin是个不稳定的蛋白，其半衰期为4小时。泛素蛋白酶抑制剂MG132或ALLN可以阻断Livin的降解，说明Livin的降解是通过泛素-蛋白酶体途径介导并发生的。
同时我们也发现，RING结构域在Livin的自身泛素化过程中起了决定性的作用，而BIR结构域则表现出对其自身降解具有某种抑制作用。
我们构建了几个BIR结构域的点突变Cys124，Trp134，His144和RING区域的缺失突变，BIR结构域的突变大大增加了Livin的不稳定性，而且突变后的Livin也不再能和Smac／DIABLO结合，从而导致其抗凋亡功能的减弱，而RING区域的缺失突变仍然可以和Smac／DIABLO结合。除泛素化降解机制外的其他的尚不可知的非泛素-蛋白酶体途径依赖的机制可能参与了BIR结构域突变体的降解，从而使BIR点突变体表现出比野生型Livin更加不稳定。
我们的研究赋予Livin一个新的重要的功能：Livin可以通过泛素-蛋白酶体途径来发挥E3泛素连接酶的功能促进促凋亡因子Smac／DIABLO的泛素化降解，从而在鬼臼乙叉甙诱导的细胞凋亡中更好的发挥其抑凋亡的功能。这为Livin
Apoptosis, also known as programmed cell death (PCD), is a gene controlled active cell suicide process that is important for the maintenance of balance of organisms. Livin (also called ML-IAP or KIAP) , a member of the inhibitor of apoptosis protein (IAP) family encodes a protein containing a single baculoviral IAP repeat (BIR) domain and a COOH-terminal RING finger domain. It has been reported that Livin directly interacts with caspase-3, -7 in vitro and caspase-9 in vivo via its BIR domain and is negatively regulated by Smac/DIABLO. Livin is a poor caspases inhibitor, the detailed mechanism underlying its anti-apoptotic function needs to be clarified and characterized. So we do the underlying research and get some conclusions.
In this report, we provided, for the first time, the evidence that Livin can act as an E3 ubiquitin ligase for targeting the degradation of Smac/DIABLO. Both BIR domain and RING finger domain of Livin are indispensable for this degradation of Smac/DIABLO in vivo and in vitro.
We also demonstrated that Livin is an unstable protein with a half-life of less than 4 hours in living cells. Degradation of Livin can be blocked by proteasome inhibitor MG132 or ALLN, suggesting that Livin is a target for ubiquitin-proteasome degradation.
Furthermore, we found that RING domain of Livin promotes its auto-ubiquitination, whereas BIR domain displays degradation-inhibitory activity.
We constructed several BIR point mutants of Cys124, Trp134, His144 to form C124A, W134A and H144A and RING deletion mutant. Mutation in the Livin BIR domain greatly enhances its instability and nullifies its binding to Smac/DIABLO, resulting in a reduced anti-apoptosis inhibition, while RING deletion mutant can still interact with Smac/DIABLO. Livin BIR mutant may
在本研究中，我们首次证实了Livin可以充当E3泛素连接酶并可以泛素化降解Smac／DIABLO。体内和体外的实验证明，Livin的BIR结构域和RING区域对于Livin泛素化降解Smac／DIABLO是必不可缺少的。
我们也发现，Livin是个不稳定的蛋白，其半衰期为4小时。泛素蛋白酶抑制剂MG132或ALLN可以阻断Livin的降解，说明Livin的降解是通过泛素-蛋白酶体途径介导并发生的。
同时我们也发现，RING结构域在Livin的自身泛素化过程中起了决定性的作用，而BIR结构域则表现出对其自身降解具有某种抑制作用。
我们构建了几个BIR结构域的点突变Cys124，Trp134，His144和RING区域的缺失突变，BIR结构域的突变大大增加了Livin的不稳定性，而且突变后的Livin也不再能和Smac／DIABLO结合，从而导致其抗凋亡功能的减弱，而RING区域的缺失突变仍然可以和Smac／DIABLO结合。除泛素化降解机制外的其他的尚不可知的非泛素-蛋白酶体途径依赖的机制可能参与了BIR结构域突变体的降解，从而使BIR点突变体表现出比野生型Livin更加不稳定。
我们的研究赋予Livin一个新的重要的功能：Livin可以通过泛素-蛋白酶体途径来发挥E3泛素连接酶的功能促进促凋亡因子Smac／DIABLO的泛素化降解，从而在鬼臼乙叉甙诱导的细胞凋亡中更好的发挥其抑凋亡的功能。这为Livin
Apoptosis, also known as programmed cell death (PCD), is a gene controlled active cell suicide process that is important for the maintenance of balance of organisms. Livin (also called ML-IAP or KIAP) , a member of the inhibitor of apoptosis protein (IAP) family encodes a protein containing a single baculoviral IAP repeat (BIR) domain and a COOH-terminal RING finger domain. It has been reported that Livin directly interacts with caspase-3, -7 in vitro and caspase-9 in vivo via its BIR domain and is negatively regulated by Smac/DIABLO. Livin is a poor caspases inhibitor, the detailed mechanism underlying its anti-apoptotic function needs to be clarified and characterized. So we do the underlying research and get some conclusions.
In this report, we provided, for the first time, the evidence that Livin can act as an E3 ubiquitin ligase for targeting the degradation of Smac/DIABLO. Both BIR domain and RING finger domain of Livin are indispensable for this degradation of Smac/DIABLO in vivo and in vitro.
We also demonstrated that Livin is an unstable protein with a half-life of less than 4 hours in living cells. Degradation of Livin can be blocked by proteasome inhibitor MG132 or ALLN, suggesting that Livin is a target for ubiquitin-proteasome degradation.
Furthermore, we found that RING domain of Livin promotes its auto-ubiquitination, whereas BIR domain displays degradation-inhibitory activity.
We constructed several BIR point mutants of Cys124, Trp134, His144 to form C124A, W134A and H144A and RING deletion mutant. Mutation in the Livin BIR domain greatly enhances its instability and nullifies its binding to Smac/DIABLO, resulting in a reduced anti-apoptosis inhibition, while RING deletion mutant can still interact with Smac/DIABLO. Livin BIR mutant may
引文
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