Mitochondria-derived Hydrogen Peroxide Selectively Enhances T Cell Receptor-initiated Signal Transduction
Mitochondria-derived Hydrogen Peroxide Selectively Enhances T Cell Receptor-initiated Signal Transduction
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DOI：
10.1074/jbc.m113.476895
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发表时间：
2013-09-06
影响因子：
4.8
通讯作者：
Levine, Alan D.
中科院分区：
文献类型：
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作者：
Gill, Tejpal;Levine, Alan D.
据报道，T细胞受体（TCR）启动的信号转导增加了细胞内活性氧的产生，如超氧化物（O-2（自由基阴离子））和过氧化氢（H2O2），作为第二信使。虽然H2O2可以通过灭活蛋白磷酸酶来调节信号转导，但细胞内H2O2作为TCR的第二信使的机制和亚细胞定位尚不清楚。抗氧化酶超氧化物歧化酶（SOD）催化高活性的O-2（自由基阴离子）分解成H2O2，从而在细胞内产生H2O2。由于带电荷的O-2（自由基阴离子）无法通过细胞膜扩散，细胞在细胞质中表达不同的SOD亚型（Cu,Zn-SOD）和线粒体（Mn-SOD），在那里它们局部清除O-2（自由基阴离子）导致H2O2的产生。在Jurkat T细胞系中，SOD的2倍细胞器特异性过表达增加了细胞内H2O2的产生，但不改变细胞内H2O2清除酶的水平，如过氧化氢酶、膜结合过氧化物还蛋白-1 （Prx1）和细胞质Prx2。我们报道，Mn-SOD的过表达增强了TCR交联后1分钟内TCR相关膜近端信号转导分子Lck、LAT、ZAP70、PLC gamma 1和SLP76的酪氨酸磷酸化。线粒体H2O2的增加通过JNK/c Junpathway特异性调节MAPK信号，而过表达Cu， Zn-SOD对这些tcr介导的信号分子没有影响。由于线粒体在TCR激活过程中转运到免疫突触，我们假设这种转运提供了选择性调节下游信号转导途径所需的有效H2O2浓度。
T cell receptor (TCR)-initiated signal transduction is reported to increase production of intracellular reactive oxygen species, such as superoxide (O-2(radical anion)) and hydrogen peroxide (H2O2), as second messengers. Although H2O2 can modulate signal transduction by inactivating protein phosphatases, the mechanism and the subcellular localization of intracellular H2O2 as a second messenger of the TCR are not known. The antioxidant enzyme superoxide dismutase (SOD) catalyzes the dismutation of highly reactive O-2(radical anion) into H2O2 and thus acts as an intracellular generator of H2O2. As charged O-2(radical anion) is unable to diffuse through intracellular membranes, cells express distinct SOD isoforms in the cytosol (Cu,Zn-SOD) and mitochondria (Mn-SOD), where they locally scavenge O-2(radical anion) leading to production of H2O2. A 2-fold organelle-specific overexpression of either SOD in Jurkat T cell lines increases intracellular production of H2O2 but does not alter the levels of intracellular H2O2 scavenging enzymes such as catalase, membrane-bound peroxiredoxin-1 (Prx1), and cytosolic Prx2. We report that overexpression of Mn-SOD enhances tyrosine phosphorylation of TCR-associated membrane proximal signal transduction molecules Lck, LAT, ZAP70, PLC gamma 1, and SLP76 within 1 min of TCR cross-linking. This increase in mitochondrial H2O2 specifically modulates MAPK signaling through the JNK/c Junpathway, whereas overexpressing Cu, Zn-SOD had no effect on any of these TCR-mediated signaling molecules. As mitochondria translocate to the immunological synapse during TCR activation, we hypothesize this translocation provides the effective concentration of H2O2 required to selectively modulate downstream signal transduction pathways.