Srivastava Smita, Banerjee Hridesh, Chaudhry Ashutosh, Khare Anupriya, Sarin Apurva, George Anna, Bal Vineeta, Durdik Jeannine M, Rath Satyajit
National Institute of Immunology, New Delhi, India.
J Immunol. 2007 Jul 15;179(2):797-803. doi: 10.4049/jimmunol.179.2.797.
Apoptosis-inducing factor (Aif) is a mitochondrial flavoprotein with multiple roles in apoptosis as well as in cellular respiration and redox regulation. The harlequin (Hq) mouse strain carries an aif locus modification causing reduced Aif expression. We demonstrate that activated CD4(+) and CD8(+) peripheral T cells from Hq mice show resistance to neglect-induced death (NID) triggered by growth factor withdrawal, but not to death induced by multiple agents that trigger DNA damage. Aif translocates to the nucleus in cells undergoing NID, and, in Hq T cell blasts, resistance to NID is associated with reduced cytosolic release of mitochondrial cytochrome c, implicating Aif in this event. In contrast, Hq T cell blasts express higher levels of CD95L, demonstrating increased susceptibility to activation-induced cell death (AICD) and apoptosis triggered by hydrogen peroxide. Superoxide scavenging protects from AICD in wild-type, but not Hq, T cell blasts, suggesting that Aif plays a crucial superoxide-scavenging role to regulate T cell AICD. Finally, the altered pattern of death susceptibility is reproduced by siRNA-mediated reduction of Aif expression in normal T cells. Thus, Aif serves nonredundant roles, both proapoptotic and antiapoptotic, in activated peripheral T cells.
凋亡诱导因子（Aif）是一种线粒体黄素蛋白，在细胞凋亡、细胞呼吸和氧化还原调节中具有多种作用。丑角（Hq）小鼠品系携带aif基因座修饰，导致Aif表达降低。我们证明，来自Hq小鼠的活化CD4(+)和CD8(+)外周T细胞对生长因子撤除引发的忽视诱导死亡（NID）具有抗性，但对多种引发DNA损伤的试剂诱导的死亡没有抗性。Aif在经历NID的细胞中易位至细胞核，并且在Hq T细胞母细胞中，对NID的抗性与线粒体细胞色素c的胞质释放减少有关，这表明Aif参与了这一过程。相反，Hq T细胞母细胞表达更高水平的CD95L，表明其对活化诱导的细胞死亡（AICD）和过氧化氢引发的凋亡更敏感。超氧化物清除可保护野生型而非Hq T细胞母细胞免受AICD，这表明Aif在调节T细胞AICD中起关键的超氧化物清除作用。最后，通过siRNA介导正常T细胞中Aif表达的降低，重现了死亡易感性的改变模式。因此，Aif在活化的外周T细胞中发挥着促凋亡和抗凋亡的非冗余作用。
