Glutamine-dependent antiapoptotic interaction of human glutaminyl-tRNA synthetase with apoptosis signal-regulating kinase 1
Glutamine-dependent antiapoptotic interaction of human glutaminyl-tRNA synthetase with apoptosis signal-regulating kinase 1
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DOI：
10.1074/jbc.m006189200
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发表时间：
2001-02-23
影响因子：
4.8
通讯作者：
Kim, S
中科院分区：
文献类型：
--
作者：
Ko, YG;Kim, EK;Kim, S
谷氨酰胺被认为是一种凋亡抑制剂，因为它可以阻断热休克、辐射和c-Myc过表达诱导的凋亡。在这里，我们证明了HeLa细胞在谷氨酰胺剥夺的条件下对Fas介导的凋亡敏感。Fas连接激活凋亡信号调节激酶1和c-Jun N-末端激酶（JNK;也称为应激激活蛋白激酶（SAPK））在Gin剥夺的细胞中表达，而在正常细胞中不表达，提示Gln可能参与了ASK 1和JNK/SAPK的活性调控。Gln抑制ASK 1的可能机制之一，我们研究了人氨酰-tRNA合成酶（QRS）与ASK 1之间的分子相互作用，发现这两个分子之间存在依赖于Gin的缔合。虽然他们的协会是通过提高谷氨酰胺浓度，他们解离Fas连接在5分钟内。协会涉及的两种酶的催化结构域。通过体外激酶和转录测定，与QRS的相互作用抑制了ASK 1活性。最后，我们已经表明，QRS抑制由ASK 1诱导的细胞死亡，并且QRS的这种抗凋亡功能被Gin剥夺所减弱，因此，QRS与ASK 1的抗凋亡相互作用受Gin的细胞浓度的正控制，而受Fas连接的负控制，这项工作的结果提供了一个可能的解释的工作机制的抗凋亡活性的Gin，并提出了一个新的功能的哺乳动物ARSs。
Glutamine has been known to be an apoptosis suppressor, since it blocks apoptosis induced by heat shock, irradiation, and c-Myc overexpression, Here, we demonstrated that HeLa cells were susceptible to Fas-mediated apoptosis under the condition of glutamine deprivation. Fas ligation activated apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK; also known as stress-activated protein kinase (SAPK)) in Gin-deprived cells but not in normal cells, suggesting that Gin might be involved in the activity control of ASK1 and JNK/SAPK, As one of the possible mechanisms for the suppressive effect of Gln on ASK1, we investigated the molecular interaction between human glutaminyl-tRNA synthetase (QRS) and ASK1 and found the Gin-dependent association of the two molecules. While their association was enhanced by the elevation of Gin concentration, they were dissociated by Fas ligation within 5 min. The association involved the catalytic domains of the two enzymes. The ASK1 activity was inhibited by the interaction with QRS as determined by in vitro kinase and transcription assays. Finally, we have shown that QRS inhibited the cell death induced by ASK1, and this antiapoptotic function of QRS was weakened by the deprivation of Gin, Thus, the antiapoptotic interaction of QRS with ASK1 is controlled positively by the cellular concentration of Gin and negatively by Fas ligation, The results of this work provide one possible explanation for the working mechanism of the antiapoptotic activity of Gin and suggest a novel function of mammalian ARSs.