Cytochrome c-induced lymphocyte death from the outside in: inhibition by serum leucine-rich alpha-2-glycoprotein-1
Cytochrome c-induced lymphocyte death from the outside in: inhibition by serum leucine-rich alpha-2-glycoprotein-1
复制标题
DOI：
10.1007/s10495-009-0412-0
复制
发表时间：
2010-02-01
期刊：
影响因子：
7.2
通讯作者：
Jemmerson, Ronald
中科院分区：
文献类型：
--
作者：
Codina, Ramil;Vanasse, Amelia;Jemmerson, Ronald
之前我们报道过血清富含亮氨酸的 α-2-糖蛋白-1 (LRG) 结合细胞色素 c (Cyt c; Cummings 等人, Apoptosis 11:1121-1129, 2009)。在这里，我们表明 LRG 与 Cyt c 的结合与 Apaf-1 相似。 LRG 和 Apaf-1 共享部分氨基酸序列，竞争结合 Cyt c，并通过 Cyt c 中赖氨酸 72 处的修饰而受到抑制。然而，与 Apaf-1 不同，LRG 在体外充当存活因子而不是促凋亡因子。通过从培养基中耗尽LRG，我们发现LRG可以防止外源Cyt c对淋巴细胞的毒性作用，否则会导致细胞凋亡表型。 LRG 以及 Cyt c 特异性抗体在不添加 Cyt c 的情况下增加了细胞活力，表明培养物中垂死细胞释放的 Cyt c 本身是有毒的。对细胞外 Cyt c 诱导的淋巴毒性的保护似乎涉及主动机制，而不是 Cyt c 的空间位阻。因此，血清LRG当与凋亡细胞释放的细胞外Cyt c结合时，充当淋巴细胞以及可能对细胞外Cyt c的毒性作用敏感的其他细胞的生存因子。
Previously we reported that serum leucine-rich alpha-2-glycoprotein-1 (LRG) binds cytochrome c (Cyt c; Cummings et al., Apoptosis 11:1121-1129, 2009). Here we show that LRG binding to Cyt c is similar to that of Apaf-1. LRG and Apaf-1 share partial amino acid sequences, compete for binding Cyt c, and are inhibited by modification at lysine 72 in Cyt c. However, in contrast to Apaf-1, LRG acts as a survival factor in vitro rather than a pro-apoptotic factor. By depleting LRG from culture medium we found that LRG protects against a toxic effect of exogenous Cyt c on lymphocytes that would otherwise result in an apoptotic phenotype. LRG, as well as antibodies specific for Cyt c, increased cell viability in the absence of added Cyt c indicating that Cyt c released by dying cells in the cultures is itself toxic. Protection from extracellular Cyt c-induced lymphotoxicity appears to involve an active mechanism rather than steric hindrance of Cyt c. Thus, serum LRG when bound to extracellular Cyt c that is released from apoptotic cells acts as a survival factor for lymphocytes and possibly other cells that are susceptible to the toxic effect of extracellular Cyt c.