Acetylation-dependent glutamate receptor GluR signalosome formation for STAT3 activation in both transcriptional and metabolism regulation.
Acetylation-dependent glutamate receptor GluR signalosome formation for STAT3 activation in both transcriptional and metabolism regulation.
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转录和代谢调节中 STAT3 激活的乙酰化依赖性谷氨酸受体 GluR 信号体形成
DOI：
10.1038/s41420-020-00389-6
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发表时间：
2021-01-14
影响因子：
7
通讯作者：
Chin YE
中科院分区：
文献类型：
--
作者：
Li XR;Cheng X;Sun J;Xu YS;Chen N;Hao Y;Huang C;Chin YE
除了它们在脑、脊髓、视网膜和外周神经系统中用于介导快速兴奋性突触传递的原始调节作用之外，由代谢型谷氨酸受体（GluR）和离子型谷氨酸受体（iGluR）组成的谷氨酸受体已经出现在癌症起始、进展和转移的生物学中具有关键作用。然而，由配体结合的GluRs介导的信号转导的确切机制尚未明确阐明。在这里，我们表明，iGluRs，GluR 1和GluR 2，乙酰化的乙酰转移酶CREB结合蛋白谷氨酸刺激细胞后，并有针对性的赖氨酰氧化酶样2脱乙酰化。乙酰化GluR 1/2募集β-arrestin 1/2和信号转导和转录激活因子3（STAT 3）形成蛋白复合物。β-arrestin 1/2和STAT 3随后都被乙酰化和活化。同时，活化的STAT 3在赖氨酸685处乙酰化，易位到线粒体以上调能量代谢相关基因转录。我们的研究结果表明，乙酰化依赖的GluR 1/2-β-arrestin 1/2-STAT 3信号体的形成是谷氨酸诱导的细胞增殖的关键。
Besides their original regulating roles in the brain, spinal cord, retina, and peripheral nervous system for mediating fast excitatory synaptic transmission, glutamate receptors consisting of metabotropic glutamate receptors (GluRs) and ionotropic glutamate receptors (iGluRs) have emerged to have a critical role in the biology of cancer initiation, progression, and metastasis. However, the precise mechanism underpinning the signal transduction mediated by ligand-bound GluRs is not clearly elucidated. Here, we show that iGluRs, GluR1 and GluR2, are acetylated by acetyltransferase CREB-binding protein upon glutamate stimulation of cells, and are targeted by lysyl oxidase-like 2 for deacetylation. Acetylated GluR1/2 recruit β-arrestin1/2 and signal transducer and activator of transcription 3 (STAT3) to form a protein complex. Both β-arrestin1/2 and STAT3 are subsequently acetylated and activated. Simultaneously, activated STAT3 acetylated at lysine 685 translocates to mitochondria to upregulate energy metabolism-related gene transcription. Our results reveal that acetylation-dependent formation of GluR1/2–β-arrestin1/2–STAT3 signalosome is critical for glutamate-induced cell proliferation.
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DOI：
10.1126/science.1190287
发表时间：
2010-08-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li N;Lee B;Liu RJ;Banasr M;Dwyer JM;Iwata M;Li XY;Aghajanian G;Duman RS
通讯作者：
Duman RS
影响因子：
4.4
作者：
Aguilera, P;Ortega, A
通讯作者：
Ortega, A
影响因子：
6.4
作者：
Liu, Jun-Wei;Kim, Myoung Sook;Sidransky, David
通讯作者：
Sidransky, David
影响因子：
50.3
作者：
Kim E;Kim M;Woo DH;Shin Y;Shin J;Chang N;Oh YT;Kim H;Rheey J;Nakano I;Lee C;Joo KM;Rich JN;Nam DH;Lee J
通讯作者：
Lee J
影响因子：
4.7
作者：
María López-Colomé A;Martínez-Lozada Z;Guillem AM;López E;Ortega A
通讯作者：
Ortega A