Department of Microbiology, University of Minnesota Medical School, Minneapolis, MN, USA.
Apoptosis. 2010 Feb;15(2):139-52. doi: 10.1007/s10495-009-0412-0.
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.
此前我们报道了富含亮氨酸的α-2-糖蛋白-1（LRG）与细胞色素 c（Cyt c；Cummings 等人，凋亡 11：1121-1129，2009）结合。在这里，我们发现 LRG 与 Cyt c 的结合类似于 Apaf-1 的结合。LRG 和 Apaf-1 共享部分氨基酸序列，竞争结合 Cyt c，并被 Cyt c 赖氨酸 72 修饰所抑制。然而，与 Apaf-1 相反，LRG 在体外作为一种生存因子而不是促凋亡因子发挥作用。通过从培养基中耗尽 LRG，我们发现 LRG 可以防止外源性 Cyt c 对淋巴细胞的毒性作用，否则会导致凋亡表型。LRG 以及针对 Cyt c 的特异性抗体在没有添加 Cyt c 的情况下增加了细胞活力，表明培养物中死亡细胞释放的 Cyt c 本身就是有毒的。从细胞外 Cyt c 诱导的淋巴毒性中得到保护似乎涉及一种主动机制，而不是 Cyt c 的空间位阻。因此，当结合到从凋亡细胞释放的细胞外 Cyt c 时，血清 LRG 作为淋巴细胞和可能对细胞外 Cyt c 的毒性作用敏感的其他细胞的生存因子发挥作用。
