Inhibition of p70 S6 kinase activity by A77 1726 induces autophagy and enhances the degradation of superoxide dismutase 1 (SOD1) protein aggregates.
Inhibition of p70 S6 kinase activity by A77 1726 induces autophagy and enhances the degradation of superoxide dismutase 1 (SOD1) protein aggregates.
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DOI：
10.1038/s41419-018-0441-0
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发表时间：
2018-03-14
影响因子：
9
通讯作者：
Xu X
中科院分区：
文献类型：
--
作者：
Sun J;Mu Y;Jiang Y;Song R;Yi J;Zhou J;Sun J;Jiao X;Prinz RA;Li Y;Xu X
自噬在降解错误折叠蛋白（如突变的超氧化物歧化酶 1 (SOD1)）方面发挥着核心作用，SOD1 在运动神经元中形成聚集体，并参与肌萎缩侧索硬化症 (ALS) 的发病机制。当 UNC-51 样激酶 1 (ULK1) 在 S555 处磷酸化并被 AMP 激活蛋白激酶 (AMPK) 激活时，自噬就会被激活。当 ULK1 在 S757 被雷帕霉素 (mTOR) 机制靶标磷酸化时，自噬会受到抑制。 p70 S6 激酶 1 (S6K1)（mTOR 下游的一种丝氨酸/苏氨酸激酶）是否也能调节自噬仍不确定。在这里，我们报道了 A77 1726（抗炎药物来氟米特的活性代谢物）对 S6K1 的抑制，诱导了 NSC34 细胞（一种杂交小鼠运动神经元细胞系）中 mTOR 反馈激活和 ULK1S757 磷酸化。出乎意料的是，A77 1726 并没有抑制自噬，而是通过增加 AMPKT172 和 ULK1S555 磷酸化来诱导自噬。使用 PF-4708671（一种特定的 S6K1 抑制剂）或 S6K1 siRNA 也进行了类似的观察。进一步的研究表明，A77 1726 通过激活 TGF-β 激活激酶 1 (TAK1) 诱导 AMPK 磷酸化。功能研究表明，A77 1726 诱导突变型 SOD1G93A 蛋白与自噬体聚集共定位，并加速 SOD1G93A 蛋白降解，而自噬相关蛋白 7 (ATG7) siRNA 抑制自噬可阻止这种降解。我们的研究表明，在 NSC34 细胞中，S6K1 抑制通过 TAK1 介导的 AMPK 激活来诱导自噬，并且通过来氟米特等小分子抑制剂阻断 S6K1 活性可能为 ALS 治疗提供新策略。
Autophagy plays a central role in degrading misfolded proteins such as mutated superoxide dismutase 1 (SOD1), which forms aggregates in motor neurons and is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Autophagy is activated when UNC-51-like kinase 1 (ULK1) is phosphorylated at S555 and activated by AMP-activated protein kinase (AMPK). Autophagy is suppressed when ULK1 is phosphorylated at S757 by the mechanistic target of rapamycin (mTOR). Whether p70 S6 kinase 1 (S6K1), a serine/threonine kinase downstream of mTOR, can also regulate autophagy remains uncertain. Here we report that inhibition of S6K1 by A77 1726, the active metabolite of an anti-inflammatory drug leflunomide, induced mTOR feedback activation and ULK1S757 phosphorylation in NSC34 cells, a hybrid mouse motoneuron cell line. Unexpectedly, A77 1726 did not suppress but rather induced autophagy by increasing AMPKT172 and ULK1S555 phosphorylation. Similar observations were made with PF-4708671, a specific S6K1 inhibitor, or with S6K1 siRNA. Further studies showed that A77 1726 induced AMPK phosphorylation by activating the TGF-β-activated kinase 1 (TAK1). Functional studies revealed that A77 1726 induced co-localization of mutant SOD1G93A protein aggregates with autophagosomes and accelerated SOD1G93A protein degradation, which was blocked by inhibition of autophagy through autophagy-related protein 7 (ATG7) siRNA. Our study suggests that S6K1 inhibition induces autophagy through TAK1-mediated AMPK activation in NSC34 cells, and that blocking S6K1 activity by a small molecule inhibitor such as leflunomide may offer a new strategy for ALS treatment.
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DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
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影响因子：
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Chen Y;Huang Q;Zhou H;Wang Y;Hu X;Li T
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Li T
影响因子：
4
作者：
de Oliveira, Gabriela P.;Maximino, Jessica R.;Chadi, Gerson
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影响因子：
4.8
作者：
Doscas, Michelle E.;Williamson, Ashley J.;Usha, Lydia;Bogachkov, Yedida;Rao, Geetha S.;Xiao, Fei;Wang, Yimin;Ruby, Carl;Kaufman, Howard;Zhou, Jingsong;Williams, James W.;Li, Yi;Xu, Xiulong
通讯作者：
Xu, Xiulong
影响因子：
5.3
作者：
Carunchio, Irene;Curcio, Livia;Zona, Cristina
通讯作者：
Zona, Cristina