PMID- 29540819 OWN - NLM STAT- MEDLINE DCOM- 20191113 LR - 20230815 IS - 2041-4889 (Electronic) VI - 9 IP - 3 DP - 2018 Mar 14 TI - Inhibition of p70 S6 kinase activity by A77 1726 induces autophagy and enhances the degradation of superoxide dismutase 1 (SOD1) protein aggregates. PG - 407 LID - 10.1038/s41419-018-0441-0 [doi] LID - 407 AB - 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. FAU - Sun, Jing AU - Sun J AD - Institute of Comparative Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China. AD - College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China. FAU - Mu, Yarong AU - Mu Y AD - College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China. FAU - Jiang, Yuanyuan AU - Jiang Y AD - College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China. FAU - Song, Ruilong AU - Song R AD - College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China. FAU - Yi, Jianxin AU - Yi J AD - Department of Physiology, Kansas City University of Medicine and Biosciences, Kansas City, MO, 64106, USA. FAU - Zhou, Jingsong AU - Zhou J AD - Department of Physiology, Kansas City University of Medicine and Biosciences, Kansas City, MO, 64106, USA. FAU - Sun, Jun AU - Sun J AUID- ORCID: 0000-0001-7465-3133 AD - Department of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA. FAU - Jiao, Xinan AU - Jiao X AD - College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China. AD - Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China. FAU - Prinz, Richard A AU - Prinz RA AD - Department of Surgery, NorthShore University Health System, Evanston, IL, 60201, USA. FAU - Li, Yi AU - Li Y AD - Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, 77030, USA. FAU - Xu, Xiulong AU - Xu X AD - Institute of Comparative Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China. xxl@yzu.edu.cn. AD - College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China. xxl@yzu.edu.cn. AD - Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China. xxl@yzu.edu.cn. AD - Department of Cell and Molecular Medicine Rush University Medical Center, Chicago, IL, 60612, USA. xxl@yzu.edu.cn. LA - eng GR - R01 AR057404/AR/NIAMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20180314 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Aniline Compounds) RN - 0 (Atg7 protein, mouse) RN - 0 (Crotonates) RN - 0 (Hydroxybutyrates) RN - 0 (Nitriles) RN - 0 (Protein Aggregates) RN - 0 (Toluidines) RN - 1C058IKG3B (teriflunomide) RN - EC 1.15.1.1 (Superoxide Dismutase-1) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.11.1 (Autophagy-Related Protein-1 Homolog) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.25 (MAP Kinase Kinase Kinases) RN - EC 2.7.11.25 (MAP kinase kinase kinase 7) RN - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases) RN - EC 6.2.1.45 (Autophagy-Related Protein 7) SB - IM MH - AMP-Activated Protein Kinase Kinases MH - Amino Acid Motifs MH - Aniline Compounds/*pharmacology MH - Animals MH - Autophagy/*drug effects MH - Autophagy-Related Protein 7/genetics/metabolism MH - Autophagy-Related Protein-1 Homolog/genetics/metabolism MH - Cell Line MH - Crotonates MH - Hydroxybutyrates/*pharmacology MH - MAP Kinase Kinase Kinases/genetics/metabolism MH - Mice MH - Nitriles MH - Protein Aggregates/drug effects MH - Protein Kinases/genetics/metabolism MH - Proteolysis/drug effects MH - Ribosomal Protein S6 Kinases, 70-kDa/*antagonists & inhibitors/chemistry/genetics/metabolism MH - Superoxide Dismutase-1/genetics/*metabolism MH - TOR Serine-Threonine Kinases/genetics/metabolism MH - Toluidines PMC - PMC5851998 COIS- The authors declare that they have no conflict of interest. EDAT- 2018/03/16 06:00 MHDA- 2019/11/14 06:00 PMCR- 2018/03/14 CRDT- 2018/03/16 06:00 PHST- 2017/11/17 00:00 [received] PHST- 2018/02/22 00:00 [accepted] PHST- 2018/02/21 00:00 [revised] PHST- 2018/03/16 06:00 [entrez] PHST- 2018/03/16 06:00 [pubmed] PHST- 2019/11/14 06:00 [medline] PHST- 2018/03/14 00:00 [pmc-release] AID - 10.1038/s41419-018-0441-0 [pii] AID - 441 [pii] AID - 10.1038/s41419-018-0441-0 [doi] PST - epublish SO - Cell Death Dis. 2018 Mar 14;9(3):407. doi: 10.1038/s41419-018-0441-0.