Deubiquitinase inhibition by WP1130 leads to ULK1 aggregation and blockade of autophagy

References

• Mizushima N, Yoshimori T, Ohsumi Y. The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol 2011; 27:107-32; PMID:21801009; http://dx.doi.org/10.1146/annurev-cellbio-092910-154005
   PubMed Web of Science ®Google Scholar
• Alers S, Löffler AS, Wesselborg S, Stork B. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol 2012; 32:2-11; PMID:22025673; http://dx.doi.org/10.1128/MCB.06159-11
   PubMed Web of Science ®Google Scholar
• Chan EY, Longatti A, McKnight NC, Tooze SA. Kinase-inactivated ULK proteins inhibit autophagy via their conserved C-terminal domains using an Atg13-independent mechanism. Mol Cell Biol 2009; 29:157-71; PMID:18936157; http://dx.doi.org/10.1128/MCB.01082-08
   PubMed Web of Science ®Google Scholar
• Ganley IG, Lam du H, Wang J, Ding X, Chen S, Jiang X. ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem 2009; 284:12297-305; PMID:19258318
   PubMed Web of Science ®Google Scholar
• Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, Iemura S, Natsume T, Takehana K, Yamada N, et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 2009; 20:1981-91; PMID:19211835; http://dx.doi.org/10.1091/mbc.E08-12-1248
   PubMed Web of Science ®Google Scholar
• Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J, Kundu M, Kim DH. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 2009; 20:1992-2003; PMID:19225151; http://dx.doi.org/10.1091/mbc.E08-12-1249
   PubMed Web of Science ®Google Scholar
• Alers S, Löffler AS, Wesselborg S, Stork B. The incredible ULKs. Cell Commun Signal 2012; 10:7; PMID:22413737; http://dx.doi.org/10.1186/1478-811X-10-7
   PubMed Web of Science ®Google Scholar
• Chan EY. mTORC1 phosphorylates the ULK1-mAtg13-FIP200 autophagy regulatory complex. Sci Signal 2009; 2:pe51; PMID:19690328; http://dx.doi.org/10.1126/scisignal.284pe51
   PubMed Web of Science ®Google Scholar
• Chan EY, Tooze SA. Evolution of Atg1 function and regulation. Autophagy 2009; 5:758-65; PMID:19411825; http://dx.doi.org/10.4161/auto.8709
   PubMed Web of Science ®Google Scholar
• Mizushima N. The role of the Atg1/ULK1 complex in autophagy regulation. Curr Opin Cell Biol 2010; 22:132-9; PMID:20056399; http://dx.doi.org/10.1016/j.ceb.2009.12.004
   PubMed Web of Science ®Google Scholar
• Wong PM, Puente C, Ganley IG, Jiang X. The ULK1 complex: sensing nutrient signals for autophagy activation. Autophagy 2013; 9:124-37; PMID:23295650; http://dx.doi.org/10.4161/auto.23323
   PubMed Web of Science ®Google Scholar
• Alers S, Löffler AS, Paasch F, Dieterle AM, Keppeler H, Lauber K, Campbell DG, Fehrenbacher B, Schaller M, Wesselborg S, et al. Atg13 and FIP200 act independently of Ulk1 and Ulk2 in autophagy induction. Autophagy 2011; 7:1423-33; PMID:22024743; http://dx.doi.org/10.4161/auto.7.12.18027
   PubMed Web of Science ®Google Scholar
• Bach M, Larance M, James DE, Ramm G. The serine/threonine kinase ULK1 is a target of multiple phosphorylation events. Biochem J 2011; 440:283-91; PMID:21819378; http://dx.doi.org/10.1042/BJ20101894
   PubMed Web of Science ®Google Scholar
• Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, Vasquez DS, Joshi A, Gwinn DM, Taylor R, et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Sci 2011; 331:456-61; PMID:21205641; http://dx.doi.org/10.1126/science.1196371
   PubMed Web of Science ®Google Scholar
• Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011; 13:132-41; PMID:21258367; http://dx.doi.org/10.1038/ncb2152
   PubMed Web of Science ®Google Scholar
• Mack HI, Zheng B, Asara JM, Thomas SM. AMPK-dependent phosphorylation of ULK1 regulates ATG9 localization. Autophagy 2012; 8:1197-214; PMID:22932492; http://dx.doi.org/10.4161/auto.20586
   PubMed Web of Science ®Google Scholar
• Shang L, Chen S, Du F, Li S, Zhao L, Wang X. Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK. Proc Natl Acad Sci U S A 2011; 108:4788-93; PMID:21383122; http://dx.doi.org/10.1073/pnas.1100844108
   PubMed Web of Science ®Google Scholar
• Lin SY, Li TY, Liu Q, Zhang C, Li X, Chen Y, Zhang SM, Lian G, Ruan K, Wang Z, et al. GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy. Sci 2012; 336:477-81; PMID:22539723; http://dx.doi.org/10.1126/science.1217032
   PubMed Web of Science ®Google Scholar
• Nazio F, Strappazzon F, Antonioli M, Bielli P, Cianfanelli V, Bordi M, Gretzmeier C, Dengjel J, Piacentini M, Fimia GM, et al. mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. Nat Cell Biol 2013; 15:406-16; PMID:23524951; http://dx.doi.org/10.1038/ncb2708
   PubMed Web of Science ®Google Scholar
• Di Bartolomeo S, Corazzari M, Nazio F, Oliverio S, Lisi G, Antonioli M, Pagliarini V, Matteoni S, Fuoco C, Giunta L, et al. The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy. J Cell Biol 2010; 191:155-68; PMID:20921139; http://dx.doi.org/10.1083/jcb.201002100
   PubMed Web of Science ®Google Scholar
• Russell RC, Tian Y, Yuan H, Park HW, Chang YY, Kim J, Kim H, Neufeld TP, Dillin A, Guan KL. ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat Cell Biol 2013; 15:741-50; PMID:23685627; http://dx.doi.org/10.1038/ncb2757
   PubMed Web of Science ®Google Scholar
• Tang HW, Wang YB, Wang SL, Wu MH, Lin SY, Chen GC. Atg1-mediated myosin II activation regulates autophagosome formation during starvation-induced autophagy. EMBO J 2011; 30:636-51; PMID:21169990 ; http://dx.doi.org/10.1038/emboj.2010.338
   PubMed Web of Science ®Google Scholar
• Papinski D, Schuschnig M, Reiter W, Wilhelm L, Barnes CA, Maiolica A, Hansmann I, Pfaffenwimmer T, Kijanska M, Stoffel I, et al. Early steps in autophagy depend on direct phosphorylation of atg9 by the atg1 kinase. Mole Cell 2014; 53:471-83; PMID:24440502; http://dx.doi.org/10.1016/j.molcel.2013.12.011
   PubMed Web of Science ®Google Scholar
• Löffler AS, Alers S, Dieterle AM, Keppeler H, Franz-Wachtel M, Kundu M, Campbell DG, Wesselborg S, Alessi DR, Stork B. Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop. Autophagy 2011; 7:696-706; PMID:21460634; http://dx.doi.org/10.4161/auto.7.7.15451
   PubMed Web of Science ®Google Scholar
• Bartholomeusz GA, Talpaz M, Kapuria V, Kong LY, Wang S, Estrov Z, Priebe W, Wu J, Donato NJ. Activation of a novel Bcr/Abl destruction pathway by WP1130 induces apoptosis of chronic myelogenous leukemia cells. Blood 2007; 109:3470-8; PMID:17202319; http://dx.doi.org/10.1182/blood-2006-02-005579
   PubMed Web of Science ®Google Scholar
• Kapuria V, Levitzki A, Bornmann WG, Maxwell D, Priebe W, Sorenson RJ, Showalter HD, Talpaz M, Donato NJ. A novel small molecule deubiquitinase inhibitor blocks Jak2 signaling through Jak2 ubiquitination. Cell Signal 2011; 23:2076-85; PMID:21855629; http://dx.doi.org/10.1016/j.cellsig.2011.08.002
   PubMed Web of Science ®Google Scholar
• Kapuria V, Peterson LF, Fang D, Bornmann WG, Talpaz M, Donato NJ. Deubiquitinase inhibition by small-molecule WP1130 triggers aggresome formation and tumor cell apoptosis. Cancer Res 2010; 70:9265-76.; PMID:21045142; http://dx.doi.org/10.1158/0008-5472.CAN-10-1530
   PubMed Web of Science ®Google Scholar
• Sun H, Kapuria V, Peterson LF, Fang D, Bornmann WG, Bartholomeusz G, Talpaz M, Donato NJ. Bcr-Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis. Blood 2011; 117:3151-62; PMID:21248063; http://dx.doi.org/10.1182/blood-2010-03-276477
   PubMed Web of Science ®Google Scholar
• Johnston JA, Ward CL, Kopito RR. Aggresomes: a cellular response to misfolded proteins. J Cell Biol 1998; 143:1883-98; PMID:9864362; http://dx.doi.org/10.1083/jcb.143.7.1883
   PubMed Web of Science ®Google Scholar
• Alemu EA, Lamark T, Torgersen KM, Birgisdottir AB, Larsen KB, Jain A, Olsvik H, Overvatn A, Kirkin V, Johansen T. ATG8 family proteins act as scaffolds for assembly of the ULK complex: sequence requirements for LC3-interacting region (LIR) motifs. J Biol Chem 2012; 287:39275-90; PMID:23043107; http://dx.doi.org/10.1074/jbc.M112.378109
   PubMed Web of Science ®Google Scholar
• Peddaboina C, Jupiter D, Fletcher S, Yap JL, Rai A, Tobin RP, Jiang W, Rascoe P, Rogers MK, Smythe WR, et al. The downregulation of Mcl-1 via USP9X inhibition sensitizes solid tumors to Bcl-xl inhibition. BMC Cancer 2012; 12:541; PMID:23171055; http://dx.doi.org/10.1186/1471-2407-12-541
   PubMed Web of Science ®Google Scholar
• Peng Z, Maxwell DS, Sun D, Bhanu Prasad BA, Schuber PT, Jr., Pal A, Ying Y, Han D, Gao L, Wang S, et al. Degrasyn-like symmetrical compounds: Possible therapeutic agents for multiple myeloma (MM-I). Bioorg Med Chem 2014; 22:1450-8; PMID:24457091 ; http://dx.doi.org/10.1016/j.bmc.2013.12.048
   PubMed Web of Science ®Google Scholar
• Wang S, Kollipara RK, Srivastava N, Li R, Ravindranathan P, Hernandez E, Freeman E, Humphries CG, Kapur P, Lotan Y, et al. Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer. Proc Natl Acad Sci U S A 2014; 111(11):4251-6; PMID:24591637; http://dx.doi.org/10.1073/pnas.1322198111
   PubMed Web of Science ®Google Scholar
• Harris DR, Mims A, Bunz F. Genetic disruption of USP9X sensitizes colorectal cancer cells to 5-fluorouracil. Cancer Biol Therapy 2012; 13:1319-24; PMID:22895071; http://dx.doi.org/10.4161/cbt.21792
   PubMed Web of Science ®Google Scholar
• Xu P, Duong DM, Seyfried NT, Cheng D, Xie Y, Robert J, Rush J, Hochstrasser M, Finley D, Peng J. Quantitative proteomics reveals the function of unconventional ubiquitin chains in proteasomal degradation. Cell 2009; 137:133-45; PMID:19345192; http://dx.doi.org/10.1016/j.cell.2009.01.041
   PubMed Web of Science ®Google Scholar
• Kobayashi S, Yoneda-Kato N, Itahara N, Yoshida A, Kato JY. The COP1 E3-ligase interacts with FIP200, a key regulator of mammalian autophagy. BMC Biochem 2013; 14:1; PMID:23289756; http://dx.doi.org/10.1186/1471-2091-14-1
   PubMed Web of Science ®Google Scholar
• Komander D, Clague MJ, Urbe S. Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 2009; 10:550-63; PMID:19626045; http://dx.doi.org/10.1038/nrm2731
   PubMed Web of Science ®Google Scholar
• Lazarus MB, Novotny CJ, Shokat KM. Structure of the Human Autophagy Initiating Kinase ULK1 in Complex with Potent Inhibitors. ACS Chem Biol 2015; 10(1):257-61; PMID:25551253; http://dx.doi.org/10.1021/cb500835z
   PubMed Web of Science ®Google Scholar