{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T07:11:57Z","timestamp":1791529917005,"version":"4.3.4"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"7652","license":[{"start":{"date-parts":[[2017,4,26]],"date-time":"2017-04-26T00:00:00Z","timestamp":1493164800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nature"],"published-print":{"date-parts":[[2017,5]]},"DOI":"10.1038\/nature22078","type":"journal-article","created":{"date-parts":[[2017,4,25]],"date-time":"2017-04-25T11:05:49Z","timestamp":1493118349000},"page":"108-111","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":340,"title":["Polyglutamine tracts regulate beclin 1-dependent autophagy"],"prefix":"10.1038","volume":"545","author":[{"given":"Avraham","family":"Ashkenazi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla F.","family":"Bento","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Ricketts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariella","family":"Vicinanza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farah","family":"Siddiqi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Pavel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferdinando","family":"Squitieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maarten C.","family":"Hardenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Imarisio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona M.","family":"Menzies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C.","family":"Rubinsztein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,4,26]]},"reference":[{"key":"BFnature22078_CR1","doi-asserted-by":"publisher","first-page":"1990","DOI":"10.1126\/science.277.5334.1990","volume":"277","author":"M DiFiglia","year":"1997","unstructured":"DiFiglia, M. et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277, 1990\u20131993 (1997)","journal-title":"Science"},{"key":"BFnature22078_CR2","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1007\/s12311-008-0013-4","volume":"7","author":"O Riess","year":"2008","unstructured":"Riess, O., R\u00fcb, U., Pastore, A., Bauer, P. & Sch\u00f6ls, L. SCA3: neurological features, pathogenesis and animal models. Cerebellum 7, 125\u2013137 (2008)","journal-title":"Cerebellum"},{"key":"BFnature22078_CR3","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1042\/BJ20071619","volume":"412","author":"S Imarisio","year":"2008","unstructured":"Imarisio, S. et al. Huntington\u2019s disease: from pathology and genetics to potential therapies. Biochem. J. 412, 191\u2013209 (2008)","journal-title":"Biochem. J."},{"key":"BFnature22078_CR4","doi-asserted-by":"publisher","first-page":"2366","DOI":"10.1073\/pnas.1221891110","volume":"110","author":"K Sathasivam","year":"2013","unstructured":"Sathasivam, K. et al. Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease. Proc. Natl Acad. Sci. USA 110, 2366\u20132370 (2013)","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFnature22078_CR5","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1038\/nature05291","volume":"443","author":"DC Rubinsztein","year":"2006","unstructured":"Rubinsztein, D. C. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443, 780\u2013786 (2006)","journal-title":"Nature"},{"key":"BFnature22078_CR6","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1038\/nature02998","volume":"431","author":"M Arrasate","year":"2004","unstructured":"Arrasate, M., Mitra, S., Schweitzer, E. S., Segal, M. R. & Finkbeiner, S. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431, 805\u2013810 (2004)","journal-title":"Nature"},{"key":"BFnature22078_CR7","doi-asserted-by":"publisher","first-page":"3605","DOI":"10.1074\/jbc.M310939200","volume":"279","author":"Y Chai","year":"2004","unstructured":"Chai, Y., Berke, S. S., Cohen, R. E. & Paulson, H. L. Poly-ubiquitin binding by the polyglutamine disease protein ataxin-3 links its normal function to protein surveillance pathways. J. Biol. Chem. 279, 3605\u20133611 (2004)","journal-title":"J. Biol. Chem."},{"key":"BFnature22078_CR8","doi-asserted-by":"publisher","first-page":"3195","DOI":"10.1093\/hmg\/ddg344","volume":"12","author":"B Burnett","year":"2003","unstructured":"Burnett, B., Li, F. & Pittman, R. N. The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity. Hum. Mol. Genet. 12, 3195\u20133205 (2003)","journal-title":"Hum. Mol. Genet."},{"key":"BFnature22078_CR9","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1002\/ana.410410408","volume":"41","author":"HL Paulson","year":"1997","unstructured":"Paulson, H. L. et al. Machado\u2013Joseph disease gene product is a cytoplasmic protein widely expressed in brain. Ann. Neurol. 41, 453\u2013462 (1997)","journal-title":"Ann. Neurol."},{"key":"BFnature22078_CR10","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1006\/nbdi.1998.0208","volume":"5","author":"Y Trottier","year":"1998","unstructured":"Trottier, Y. et al. Heterogeneous intracellular localization and expression of ataxin-3. Neurobiol. Dis. 5, 335\u2013347 (1998)","journal-title":"Neurobiol. Dis."},{"key":"BFnature22078_CR11","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1038\/45257","volume":"402","author":"XH Liang","year":"1999","unstructured":"Liang, X. H. et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402, 672\u2013676 (1999)","journal-title":"Nature"},{"key":"BFnature22078_CR12","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1038\/ng1362","volume":"36","author":"B Ravikumar","year":"2004","unstructured":"Ravikumar, B. et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36, 585\u2013595 (2004)","journal-title":"Nat. Genet."},{"key":"BFnature22078_CR13","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1093\/brain\/awp292","volume":"133","author":"FM Menzies","year":"2010","unstructured":"Menzies, F. M. et al. Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. Brain 133, 93\u2013104 (2010)","journal-title":"Brain"},{"key":"BFnature22078_CR14","doi-asserted-by":"publisher","first-page":"5720","DOI":"10.1093\/emboj\/19.21.5720","volume":"19","author":"Y Kabeya","year":"2000","unstructured":"Kabeya, Y. et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J . 19, 5720\u20135728 (2000)","journal-title":"EMBO J"},{"key":"BFnature22078_CR15","doi-asserted-by":"publisher","first-page":"1102","DOI":"10.1038\/ncb1007-1102","volume":"9","author":"Z Xie","year":"2007","unstructured":"Xie, Z. & Klionsky, D. J. Autophagosome formation: core machinery and adaptations. Nat. Cell Biol. 9, 1102\u20131109 (2007)","journal-title":"Nat. Cell Biol."},{"key":"BFnature22078_CR16","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1146\/annurev-biochem-052709-094552","volume":"80","author":"H Weidberg","year":"2011","unstructured":"Weidberg, H., Shvets, E. & Elazar, Z. Biogenesis and cargo selectivity of autophagosomes. Annu. Rev. Biochem. 80, 125\u2013156 (2011)","journal-title":"Annu. Rev. Biochem."},{"key":"BFnature22078_CR17","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1042\/bj20030826","volume":"376","author":"A Tassa","year":"2003","unstructured":"Tassa, A., Roux, M. P., Attaix, D. & Bechet, D. M. Class III phosphoinositide 3-kinase--Beclin1 complex mediates the amino acid-dependent regulation of autophagy in C2C12 myotubes. Biochem. J. 376, 577\u2013586 (2003)","journal-title":"Biochem. J."},{"key":"BFnature22078_CR18","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1080\/15548627.2015.1034404","volume":"11","author":"R He","year":"2015","unstructured":"He, R., Peng, J., Yuan, P., Xu, F. & Wei, W. Divergent roles of BECN1 in LC3 lipidation and autophagosomal function. Autophagy 11, 740\u2013747 (2015)","journal-title":"Autophagy"},{"key":"BFnature22078_CR19","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1016\/j.molcel.2014.05.021","volume":"55","author":"HC Dooley","year":"2014","unstructured":"Dooley, H. C. et al. WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1. Mol. Cell 55, 238\u2013252 (2014)","journal-title":"Mol. Cell"},{"key":"BFnature22078_CR20","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/j.molcel.2014.12.007","volume":"57","author":"M Vicinanza","year":"2015","unstructured":"Vicinanza, M. et al. PI(5)P regulates autophagosome biogenesis. Mol. Cell 57, 219\u2013234 (2015)","journal-title":"Mol. Cell"},{"key":"BFnature22078_CR21","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1016\/j.molcel.2011.08.025","volume":"44","author":"W Kim","year":"2011","unstructured":"Kim, W. et al. Systematic and quantitative assessment of the ubiquitin-modified proteome. Mol. Cell 44, 325\u2013340 (2011)","journal-title":"Mol. Cell"},{"key":"BFnature22078_CR22","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1038\/ncb3101","volume":"17","author":"YN Rui","year":"2015","unstructured":"Rui, Y. N. et al. Huntingtin functions as a scaffold for selective macroautophagy. Nat. Cell Biol. 17, 262\u2013275 (2015)","journal-title":"Nat. Cell Biol."},{"key":"BFnature22078_CR23","doi-asserted-by":"publisher","first-page":"14474","DOI":"10.1074\/jbc.M600364200","volume":"281","author":"M Shibata","year":"2006","unstructured":"Shibata, M. et al. Regulation of intracellular accumulation of mutant huntingtin by beclin 1. J. Biol. Chem. 281, 14474\u201314485 (2006)","journal-title":"J. Biol. Chem."},{"key":"BFnature22078_CR24","doi-asserted-by":"publisher","first-page":"2799","DOI":"10.1093\/hmg\/9.19.2799","volume":"9","author":"F Trettel","year":"2000","unstructured":"Trettel, F. et al. Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells. Hum. Mol. Genet . 9, 2799\u20132809 (2000)","journal-title":"Hum. Mol. Genet"},{"key":"BFnature22078_CR25","doi-asserted-by":"publisher","first-page":"1400","DOI":"10.1093\/brain\/awr047","volume":"134","author":"I Nascimento-Ferreira","year":"2011","unstructured":"Nascimento-Ferreira, I. et al. Overexpression of the autophagic beclin-1 protein clears mutant ataxin-3 and alleviates Machado\u2013Joseph disease. Brain 134, 1400\u20131415 (2011)","journal-title":"Brain"},{"key":"BFnature22078_CR26","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/j.tcb.2015.05.004","volume":"25","author":"B Levine","year":"2015","unstructured":"Levine, B., Liu, R., Dong, X. & Zhong, Q. Beclin orthologs: integrative hubs of cell signaling, membrane trafficking, and physiology. Trends Cell Biol . 25, 533\u2013544 (2015)","journal-title":"Trends Cell Biol"},{"key":"BFnature22078_CR27","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1006\/bbrc.1997.7337","volume":"238","author":"O Onodera","year":"1997","unstructured":"Onodera, O. et al. Oligomerization of expanded-polyglutamine domain fluorescent fusion proteins in cultured mammalian cells. Biochem. Biophys. Res. Commun. 238, 599\u2013605 (1997)","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"BFnature22078_CR28","doi-asserted-by":"publisher","first-page":"9310","DOI":"10.1073\/pnas.152101299","volume":"99","author":"Y Chai","year":"2002","unstructured":"Chai, Y., Shao, J., Miller, V. M., Williams, A. & Paulson, H. L. Live-cell imaging reveals divergent intracellular dynamics of polyglutamine disease proteins and supports a sequestration model of pathogenesis. Proc. Natl Acad. Sci. USA 99, 9310\u20139315 (2002)","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFnature22078_CR29","doi-asserted-by":"publisher","first-page":"19211","DOI":"10.1073\/pnas.0810452105","volume":"105","author":"Q Sun","year":"2008","unstructured":"Sun, Q. et al. Identification of Barkor as a mammalian autophagy-specific factor for Beclin 1 and class III phosphatidylinositol 3-kinase. Proc. Natl Acad. Sci. USA 105, 19211\u201319216 (2008)","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFnature22078_CR30","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1016\/j.molcel.2012.05.040","volume":"47","author":"S Luo","year":"2012","unstructured":"Luo, S. et al. Bim inhibits autophagy by recruiting Beclin 1 to microtubules. Mol. Cell 47, 359\u2013370 (2012)","journal-title":"Mol. Cell"},{"key":"BFnature22078_CR31","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.jns.2009.11.003","volume":"290","author":"M Eriguchi","year":"2010","unstructured":"Eriguchi, M. et al. alpha Pix enhances mutant huntingtin aggregation. J. Neurol. Sci. 290, 80\u201385 (2010)","journal-title":"J. Neurol. Sci."},{"key":"BFnature22078_CR32","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1038\/nchembio.1790","volume":"11","author":"M Jimenez-Sanchez","year":"2015","unstructured":"Jimenez-Sanchez, M. et al. siRNA screen identifies QPCT as a druggable target for Huntington\u2019s disease. Nat. Chem. Biol. 11, 347\u2013354 (2015)","journal-title":"Nat. Chem. Biol."},{"key":"BFnature22078_CR33","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.4161\/auto.20284","volume":"8","author":"C Zhou","year":"2012","unstructured":"Zhou, C. et al. Monitoring autophagic flux by an improved tandem fluorescent-tagged LC3 (mTagRFP-mWasabi-LC3) reveals that high-dose rapamycin impairs autophagic flux in cancer cells. Autophagy 8, 1215\u20131226 (2012)","journal-title":"Autophagy"},{"key":"BFnature22078_CR34","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1093\/hmg\/8.3.397","volume":"8","author":"G Schilling","year":"1999","unstructured":"Schilling, G. et al. Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum. Mol. Genet. 8, 397\u2013407 (1999)","journal-title":"Hum. Mol. Genet."},{"key":"BFnature22078_CR35","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1016\/S0076-6879(99)09045-X","volume":"309","author":"SW Davies","year":"1999","unstructured":"Davies, S. W. et al. Detection of polyglutamine aggregation in mouse models. Methods Enzymol . 309, 687\u2013701 (1999)","journal-title":"Methods Enzymol"},{"key":"BFnature22078_CR36","doi-asserted-by":"publisher","first-page":"1098","DOI":"10.1126\/science.1106148","volume":"307","author":"DD Sarbassov","year":"2005","unstructured":"Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt\/PKB by the rictor\u2013mTOR complex. Science 307, 1098\u20131101 (2005)","journal-title":"Science"},{"key":"BFnature22078_CR37","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/j.cell.2011.08.037","volume":"147","author":"J Liu","year":"2011","unstructured":"Liu, J. et al. Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13. Cell 147, 223\u2013234 (2011)","journal-title":"Cell"},{"key":"BFnature22078_CR38","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1042\/BJ20090428","volume":"422","author":"GR Hammond","year":"2009","unstructured":"Hammond, G. R., Schiavo, G. & Irvine, R. F. Immunocytochemical techniques reveal multiple, distinct cellular pools of PtdIns4P and PtdIns(4,5)P(2). Biochem. J. 422, 23\u201335 (2009)","journal-title":"Biochem. J."},{"key":"BFnature22078_CR39","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1038\/cr.2012.24","volume":"22","author":"W Huang","year":"2012","unstructured":"Huang, W. et al. Crystal structure and biochemical analyses reveal Beclin 1 as a novel membrane binding protein. Cell Res. 22, 473\u2013489 (2012)","journal-title":"Cell Res."},{"issue":"6257","key":"BFnature22078_CR40","doi-asserted-by":"publisher","first-page":"aac7365","DOI":"10.1126\/science.aac7365","volume":"350","author":"K. Rostislavleva","year":"2015","unstructured":"Rostislavleva, K. et al. Structure and flexibility of the endosomal Vps34 complex reveals the basis of its function on membranes. Science 350, aac7365 (2015)","journal-title":"Science"}],"container-title":["Nature"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.nature.com\/articles\/nature22078.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/nature22078","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/doifinder\/10.1038\/nature22078","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"http:\/\/www.nature.com\/articles\/nature22078.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,18]],"date-time":"2023-05-18T14:01:22Z","timestamp":1684418482000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/nature22078"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,26]]},"references-count":40,"journal-issue":{"issue":"7652","published-print":{"date-parts":[[2017,5]]}},"alternative-id":["BFnature22078"],"URL":"https:\/\/doi.org\/10.1038\/nature22078","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.727549875.793531585","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.727549875.793531539","asserted-by":"object"}]},"ISSN":["0028-0836","1476-4687"],"issn-type":[{"value":"0028-0836","type":"print"},{"value":"1476-4687","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,26]]},"assertion":[{"value":"10 November 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 March 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 April 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"F.M.M. is currently an employee of Eli Lilly & Co. Ltd.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}