The Noxa/Mcl-1 axis regulates susceptibility to apoptosis under glucose limitation in dividing T cells
The Noxa/Mcl-1 axis regulates susceptibility to apoptosis under glucose limitation in dividing T cells
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DOI：
10.1016/j.immuni.2006.03.018
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发表时间：
2006-06-01
期刊：
影响因子：
32.4
通讯作者：
Eldering, Eric
中科院分区：
文献类型：
--
作者：
Alves, Nuno L.;Derks, Ingrid A. M.;Eldering, Eric
在淋巴细胞发育过程中，细胞的存活和凋亡对细胞的持续存在和增殖进行着严格的调控。在Bcl - 2家族中，不同的仅含BH3结构域的促凋亡成员，如Bid、Bim和Puma，似乎在特定的细胞死亡途径中发挥作用。我们发现，有丝分裂原激活后的初始人类T细胞，除了预期的起保护作用的Bcl - 2成员外，还以一种不依赖p53的方式迅速上调仅含BH3结构域的蛋白Noxa。在葡萄糖受限的情况下，Noxa的特定作用变得明显，并且涉及与不稳定的Bcl - 2同源物Mcl - 1的相互作用。敲低Noxa或Mcl - 1分别导致对葡萄糖剥夺诱导的凋亡产生保护作用或易感性。Mcl - 1水平的下降和凋亡的诱导与Noxa水平呈负相关，并且可通过重新添加葡萄糖来阻止。我们提出，Noxa/Mcl - 1轴是分裂细胞中的一种凋亡调节因子，处于一种选择性途径中，其作用是抑制淋巴细胞增殖，并且可由葡萄糖剥夺触发。
Throughout lymphocyte development, cellular persistence and expansion are tightly regulated by survival and apoptosis. Within the Bcl-2 family, distinct apoptogenic BH3-only members like Bid, Bim, and Puma appear to function in specific cell death pathways. We found that naive human T cells after mitogenic activation, apart from expected protective Bcl-2 members, also rapidly upregulate the BH3-only protein Noxa in a p53-independent fashion. The specific role of Noxa became! apparent during glucose limitation and involves interaction with the labile Bcl-2 homolog Mcl-1. Knockdown of Noxa or Mcl-1 results in protection or susceptibility, respectively, to apoptosis induced by glucose deprivation. Declining Mcl-1 levels and apoptosis induction are inversely correlated to Noxa levels and prevented by readdition of glucose. We propose that the Noxa/Mcl-1 axis is an apoptosis rheostat in dividing cells, in a selective pathway that functions to restrain lymphocyte expansion and can be triggered by glucose deprivation.