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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Xiulong Xu1,2,3,8, Jing Sun1,2, Ruilong Song4, Michelle E. Doscas3, Ashley J. Williamson5, Jingsong Zhou6, Jun Sun7, Xinan Jiao8,9, Xiufan Liu9,10, Yi Li11
1Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, P. R. China
2College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, P. R. China
3Department of Anatomy and Cell Biology Rush University Medical Center, Chicago, IL 60612, USA
4Core Facility, Yangzhou University, Yangzhou 225009, Jiangsu Province, P. R. China
5Rush Medical College, Chicago, IL 60612, USA
6Department of Physiology, Kansas City University of Medicine and Biosciences, Kansas City, MO 64106, USA
7Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
8Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou 225009, Jiangsu Province, China
9Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou 225009, Jiangsu Province, China
10Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
11Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
Keywords: p70 S6 kinase ULK, autophagy, leflunomide, mTOR
Received: August 10, 2016 Accepted: February 03, 2017 Published: March 31, 2017
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.
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