Stress-induced inhibition of nonsense-mediated RNA decay regulates intracellular cystine transport and intracellular glutathione through regulation of the cystine/glutamate exchanger SLC7A11.
Stress-induced inhibition of nonsense-mediated RNA decay regulates intracellular cystine transport and intracellular glutathione through regulation of the cystine/glutamate exchanger SLC7A11.
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SLC7A11编码xCT胱氨酸/谷氨酸氨基酸运输系统的一个亚基，在谷胱甘肽的产生和保护细胞免受氧化应激中起关键作用。SLC7A11的表达促进肿瘤发生和化疗耐药，但尽管SLC7A11先前已被发现在缺氧细胞中上调，但其调控尚未完全描述。我们最近的研究表明，无义介导的RNA衰变（NMD）被肿瘤微环境（包括缺氧）产生的细胞应激所抑制，并增强了肿瘤的发生。在这里，我们证明了各种细胞应激对NMD的抑制导致SLC7A11 mRNA和蛋白的稳定和上调。抑制NMD和上调SLC7A11增加了细胞内胱氨酸运输，增加了细胞内半胱氨酸和谷胱甘肽的水平。因此，抑制NMD通过上调SLC7A11来保护细胞免受氧化应激。我们的研究共同确定了SLC7A11的动态调控机制，通过NMD的应激抑制调控，并进一步证明NMD的抑制是一种适应性反应。
SLC7A11 encodes a subunit of the xCT cystine/glutamate amino acid transport system and plays a critical role in the generation of glutathione and the protection of cells from oxidative stress. Expression of SLC7A11 promotes tumorigenesis and chemotherapy resistance, but while SLC7A11 has been previously noted to be upregulated in hypoxic cells its regulation has not been fully delineated. We have recently shown that nonsense mediated RNA decay (NMD) is inhibited by cellular stresses generated by the tumor microenvironment, including hypoxia, and augments tumorigenesis. Here we demonstrate that the inhibition of NMD by various cellular stresses leads to the stabilization and upregulation of SLC7A11 mRNA and protein. The inhibition of NMD and upregulation of SLC7A11 augments intracellular cystine transport, and increases intracellular levels of cysteine and glutathione. Accordinglyy, the inhibition of NMD protects cells against oxidative stress via SLC7A11 upregulation. Together our studies identify a mechanism for the dynamic regulation of SLC7A11, through the stress-inhibited regulation of NMD, and add to the growing evidence that the inhibition of NMD is an adaptive response.
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DOI：
10.1083/jcb.200611086
发表时间：
2007-09-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Durand S;Cougot N;Mahuteau-Betzer F;Nguyen CH;Grierson DS;Bertrand E;Tazi J;Lejeune F
通讯作者：
Lejeune F
影响因子：
28.2
作者：
Cantor JR;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
50.3
作者：
Ishimoto, Takatsugu;Nagano, Osamu;Saya, Hideyuki
通讯作者：
Saya, Hideyuki
影响因子：
16
作者：
Harding, HP;Novoa, I;Ron, D
通讯作者：
Ron, D
影响因子：
29
作者：
Ahlqvist, Kati J.;Hamalainen, Riikka H.;Suomalainen, Anu
通讯作者：
Suomalainen, Anu