期刊
CELL DEATH & DISEASE
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41419-018-0441-0
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类别
资金
- China Postdoctoral Science Foundation [2015M581873]
- Natural Science Foundation of Jiangsu Province [BK20150450]
- Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry [2015311]
- Natural Science Foundation of China [81672643]
- College of Veterinary Medicine, Yangzhou University
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- NIH [R01 AR057404]
- Department of Defense grant [BC151736P1]
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 ULK1(S757) phosphorylation in NSC34 cells, a hybrid mouse motoneuron cell line. Unexpectedly, A77 1726 did not suppress but rather induced autophagy by increasing AMPK(T172) and ULK1(S555) 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-beta-activated kinase 1 (TAK1). Functional studies revealed that A77 1726 induced co-localization of mutant SOD1(G93A) protein aggregates with autophagosomes and accelerated SOD1(G93A) 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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