Inhibition of p70 S6 kinase (S6K1) activity by A77 1726, the active metabolite of leflunomide, induces autophagy through TAK1-mediated AMPK and JNK activation.
Inhibition of p70 S6 kinase (S6K1) activity by A77 1726, the active metabolite of leflunomide, induces autophagy through TAK1-mediated AMPK and JNK activation.
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DOI：
10.18632/oncotarget.16737
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发表时间：
2017-05-02
期刊：
影响因子：
--
通讯作者：
Li Y
中科院分区：
文献类型：
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作者：
Xu X;Sun J;Song R;Doscas ME;Williamson AJ;Zhou J;Sun J;Jiao X;Liu X;Li Y
MTOR激活通过磷酸化S757处的ULK1并抑制其酶活性来抑制自噬。在这里，我们报道了两种p70 S6激酶(S6K1)抑制剂(免疫抑制药物来氟米特的活性代谢物PF-4708671和A771726)或S6K1基因敲除对PI-3激酶途径mTOR的反馈激活，但不抑制而是诱导了自噬。抑制S6K1活性导致AMPK的磷酸化和激活，然后在S555使ULK1磷酸化。虽然mTOR反馈激活导致ULK1在S757的磷酸化增加，但这种修饰没有破坏ULK1-AMPK的相互作用，也没有抑制ULK1 S555的磷酸化和自噬的诱导。此外，抑制S6K1活性导致JNK激活，这也有助于自噬。TAK1的特异性抑制剂5Z-7-oxozeaenol或TAK1 siRNA可阻断A77 1726诱导的AMPK和JNK的激活以及LC3的脂化。综上所述，我们的研究确立了S6K1是PI-3激酶途径中的一个关键角色，通过以TAK1依赖的方式抑制AMPK和JNK来抑制自噬。
mTOR activation suppresses autophagy by phosphorylating ULK1 at S757 and suppressing its enzymatic activity. Here we report that feedback activation of mTOR in the PI-3 kinase pathway by two p70 S6 kinase (S6K1) inhibitors (PF-4708671 and A77 1726, the active metabolite of an immunosuppressive drug leflunomide) or by S6K1 knockdown did not suppress but rather induced autophagy. Suppression of S6K1 activity led to the phosphorylation and activation of AMPK, which then phosphorylated ULK1 at S555. While mTOR feedback activation led to increased phosphorylation of ULK1 at S757, this modification did not the disrupt ULK1-AMPK interaction nor dampen ULK1 S555 phosphorylation and the induction of autophagy. In addition, inhibition of S6K1 activity led to JNK activation, which also contributed to autophagy. 5Z-7-oxozeaenol, a specific inhibitor of TAK1, or TAK1 siRNA blocked A77 1726-induced activation of AMPK and JNK, and LC3 lipidation. Taken together, our study establishes S6K1 as a key player in the PI-3 kinase pathway to suppress autophagy through inhibiting AMPK and JNK in a TAK1-dependent manner.