Autophagy and human diseases

Cell Research

Volumn 24, Issue 1, 2014, Pages 69-79

  Jiang, Peidu ^a,b   Mizushima, Noboru ^a,b  

^a UNIVERSITY OF TOKYO   (Japan)

^b TOKYO MEDICAL AND DENTAL UNIVERSITY   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

PROTEIN SERINE THREONINE KINASE; SIGNAL PEPTIDE;

AUTOPHAGY; DEGENERATIVE DISEASE; GENETICS; HUMAN; LYSOSOME; LYSOSOME STORAGE DISEASE; METABOLISM; MITOPHAGY; NEOPLASM; PATHOLOGY; PHYSIOLOGY; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM;

AUTOPHAGY; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; LYSOSOMAL STORAGE DISEASES; LYSOSOMES; MITOCHONDRIAL DEGRADATION; NEOPLASMS; NEURODEGENERATIVE DISEASES; POLYMORPHISM, SINGLE NUCLEOTIDE; PROTEIN-SERINE-THREONINE KINASES;

EID: 84891738225     PISSN: 10010602     EISSN: 17487838     Source Type: Journal    
DOI: 10.1038/cr.2013.161     Document Type: Review

References (144)

1. de Duve C, Wattiaux R. Functions of lysosomes. Annu Rev Physiol 1966; 28:435-492.
2. Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell 2011; 147:728-741.
3. Kaushik S, Cuervo AM. Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol 2012; 22:407-417.
4. Mizushima N, Levine B. Autophagy in mammalian development and differentiation. Nat Cell Biol 2010; 12:823-830.
5. Rabinowitz JD, White E. Autophagy and metabolism. Science 2010; 330:1344-1348.
6. Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature 2011; 469:323-335.
7. Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. N Engl J Med 2013; 368:651-662.
8. Rubinsztein DC, Mario G, Kroemer G. Autophagy and aging. Cell 2011; 146:682-695.
9. White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer 2012; 12:401-410.
10. Murrow L, Debnath J. Autophagy as a stress-response and quality-control mechanism: implications for cell injury and human disease. Annu Rev Pathol Mech Dis 2013; 8:105-137.
11. Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med 2013; 19:983-997.
12. Haack TB, Hogarth P, Kruer MC, et al. Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA. Am J Hum Genet 2012; 91:1144-1149.
13. Saitsu H, Nishimura T, Muramatsu K, et al. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat Genet 2013; 45:445-449.
14. Schneider SA, Bhatia KP. Syndromes of neurodegeneration with brain iron accumulation. Semin Pediatr Neurol 2012; 19:57-66.
15. Schneider S, Zorzi G, Nardocci N. Pathophysiology and treatment of neurodegeneration with brain iron accumulation in the pediatric population. Curr Treat Options Neurol 2013; 15:652-667.
16. Guan J, Stromhaug PE, George MD, et al. Cvt18/Gsa12 is required for cytoplasm-to-vacuole transport, pexophagy, and autophagy in Saccharomyces cerevisiae and Pichia pastoris. Mol Biol Cell 2001; 12:3821-3838.
17. Proikas-Cezanne T, Waddell S, Gaugel A, et al. WIPI-1? (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy. Oncogene 2004; 23:9314-9325.
18. Polson HE, de Lartigue J, Rigden DJ, et al. Mammalian Atg18 (WIPI2) localizes to omegasome-anchored phagophores and positively regulates LC3 lipidation. Autophagy 2010; 6:506-522.
19. Lu Q, Yang P, Huang X, et al. The WD40 repeat PtdIns(3)Pbinding protein EPG-6 regulates progression of omegasomes to autophagosomes. Dev Cell 2011; 21:343-357.
20. Dove SK, Piper RC, McEwen RK, et al. Svp1p defines a family of phosphatidylinositol 3,5-bisphosphate effectors. EMBO J 2004; 23:1922-1933.
21. Obara K, Sekito T, Niimi K, Ohsumi Y. The Atg18-Atg2 complex is recruited to autophagic membranes via phosphatidylinositol 3-phosphate and exerts an essential function. J Biol Chem 2008; 283:23972-23980.
22. Velikkakath AK, Nishimura T, Oita E, Ishihara N, Mizushima N. Mammalian Atg2 proteins are essential for autophagosome formation and important for regulation of size and distribution of lipid droplets. Mol Biol Cell 2012; 23:896-909.
23. Baskaran S, Ragusa MJ, Boura E, Hurley JH. Two-site recognition of phosphatidylinositol 3-phosphate by PROPPINs in autophagy. Mol Cell 2012; 47:339-348.
24. Krick R, Busse RA, Scacioc A, et al. Structural and functional characterization of the two phosphoinositide binding sites of PROPPINs, a ?-propeller protein family. Proc Natl Acad Sci USA 2012; 109:E2042-2049.
25. Watanabe Y, Kobayashi T, Yamamoto H, et al. Structurebased analyses reveal distinct binding sites for Atg2 and phosphoinositides in Atg18. J Biol Chem 2012; 287:31681-31690.
26. Hayflick SJ, Kruer MC, Gregory A, et al. Beta-propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation. Brain 2013; 136:1708-1717.
27. Cullup T, Kho AL, Dionisi-Vici C, et al. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nat Genet 2013; 45:83-87.
28. del Campo M, Hall BD, Aeby A, et al. Albinism and agenesis of the corpus callosum with profound developmental delay: Vici syndrome, evidence for autosomal recessive inheritance. Am J Med Genet 1999; 85:479-485.
29. Chiyonobu T, Yoshihara T, Fukushima Y, et al. Sister and brother with Vici syndrome: agenesis of the corpus callosum, albinism, and recurrent infections. Am J Med Genet 2002; 109:61-66.
30. zkale M, Erol I, Gm? A, zkale Y, Alehan F. Vici syndrome associated with sensorineural hearing loss and laryngomalacia. Pediatr Neurol 2012; 47:375-378.
31. Said E, Soler D, Sewry C. Vici syndrome-A rapidly progressive neurodegenerative disorder with hypopigmentation, immunodeficiency and myopathic changes on muscle biopsy. Am J Med Genet A 2012; 158A:440-444.
32. Tian Y, Li Z, Hu W, et al. Celegans screen identifies autophagy genes specific to multicellular organisms. Cell 2010; 141:1042-1055.
33. Zhao H, Zhao YG, Wang X, et al. Mice deficient in Epg5 exhibit selective neuronal vulnerability to degeneration. J Cell Biol 2013; 200:731-741.
34. Zhao YG, Zhao H, Sun H, Zhang H. Role of Epg5 in selective neurodegeneration and Vici syndrome. Autophagy 2013; 9:1258-1262.
35. Oz-Levi D, Ben-Zeev B, Ruzzo EK, et al. Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis. Am J Hum Genet 2012; 91:1065-1072.
36. Depienne C, Stevanin G, Brice A, Durr A. Hereditary spastic paraplegias: an update. Curr Opin Neurol 2007; 20:674-680.
37. Schle R, Schls L. Genetics of hereditary spastic paraplegias. Semin Neurol 2011; 31:484-493.
38. Blackstone C. Cellular pathways of hereditary spastic paraplegia. Annu Rev Neurosci 2012; 35:25-47.
39. Behrends C, Sowa ME, Gygi SP, Harper JW. Network organization of the human autophagy system. Nature 2010; 466:68-76.
40. Ogawa M, Yoshikawa Y, Kobayashi T, et al. A Tecpr1- dependent selective autophagy pathway targets bacterial pathogens. Cell Host Microbe 2011; 9:376-389.
41. Chen D, Fan W, Lu Y, et al. A mammalian autophagosome maturation mechanism mediated by TECPR1 and the Atg12- Atg5 conjugate. Mol Cell 2012; 45:629-641.
42. Huizing M, Hess R, Dorward H, et al. Cellular, molecular and clinical characterization of patients with Hermansky- Pudlak syndrome type 5. Traffic 2004; 5:711-722.
43. Helip-Wooley A, Westbroek W, Dorward HM, et al. Improper trafficking of melanocyte-specific proteins in Hermansky- Pudlak syndrome type-5. J Invest Dermatol 2007; 127:1471-1478.
44. Vantaggiato C, Crimella C, Airoldi G, et al. Defective autophagy in spastizin mutated patients with hereditary spastic paraparesis type 15. Brain 2013; 136:3119-3139.
45. Hanein S, Martin E, Boukhris A, et al. Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome. Am J Hum Genet 2008; 82:992-1002.
46. Itakura E, Kishi C, Inoue K, Mizushima N. Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell 2008; 19:5360-5372.
47. Matsunaga K, Saitoh T, Tabata K, et al. Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 2009; 11:385-396.
48. Sun Q, Westphal W, Wong KN, Tan I, Zhong Q. Rubicon controls endosome maturation as a Rab7 effector. Proc Natl Acad Sci USA 2010; 107:19338-19343.
49. Lee G, Liang C, Park G, et al. UVRAG is required for organ rotation by regulating Notch endocytosis in Drosophila. Dev Biol 2011; 356:588-597.
50. Fahn S. Description of Parkinsons disease as a clinical syndrome. Ann N Y Acad Sci 2003; 991:1-14.
51. Trinh J, Farrer M. Advances in the genetics of Parkinson disease. Nat Rev Neurol 2013; 9:445-454.
52. Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998; 392:605-608.
53. Valente EM, Bentivoglio AR, Dixon PH, et al. Localization of a novel locus for autosomal recessive early-onset parkinsonism, PARK6, on human chromosome 1p35-p36. Am J Hum Genet 2001; 68:895-900.
54. Valente EM, Abou-Sleiman PM, Caputo V, et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 2004; 304:1158-1160.
55. Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 2008; 183:795-803.
56. Matsuda N, Sato S, Shiba K, et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 2010; 189:211-221.
57. Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol 2011; 12:9-14.
58. Schapira AH. Mitochondria in the aetiology and pathogenesis of Parkinsons disease. Lancet Neurol 2008; 7:97-109.
59. Saita S, Shirane M, Nakayama KI. Selective escape of proteins from the mitochondria during mitophagy. Nat Commun 2013; 4:1410.
60. Tanaka A, Cleland MM, Xu S, et al. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol 2010; 191:1367-1380.
61. Chan NC, Salazar AM, Pham AH, et al. Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum Mol Genet 2011; 20:1726-1737.
62. Yoshii SR, Kishi C, Ishihara N, Mizushima N. Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane. J Biol Chem 2011; 286:19630-19640.
63. Goldberg MS, Fleming SM, Palacino JJ, et al. Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem 2003; 278:43628-43635.
64. Perez FA, Palmiter RD. Parkin-deficient mice are not a robust model of parkinsonism. Proc Natl Acad Sci USA 2005; 102:2174-2179.
65. Kitada T, Tong Y, Gautier CA, Shen J. Absence of nigral degeneration in aged parkin/DJ-1/PINK1 triple knockout mice. J Neurochem 2009; 111:696-702.
66. Lieberman AP, Puertollano R, Raben N, et al. Autophagy in lysosomal storage disorders. Autophagy 2012; 8:719-730.
67. Platt FM, Boland B, van der Spoel AC. Lysosomal storage disorders: the cellular impact of lysosomal dysfunction. J Cell Biol 2012; 199:723-734.
68. Boustany RM. Lysosomal storage diseases-the horizon expands. Nat Rev Neurol 2013; 9:583-598.
69. Janku F, McConkey DJ, Hong DS, Kurzrock R. Autophagy as a target for anticancer therapy. Nat Rev Clin Oncol 2011; 8:528-539.
70. Saito H, Inazawa J, Saito S, et al. Detailed deletion mapping of chromosome 17q in ovarian and breast cancers: 2-cM region on 17q21.3 often and commonly deleted in tumors. Cancer Res 1993; 53:3382-3385.
71. Gao X, Zacharek A, Salkowski A, et al. Loss of heterozygosity of the BRCA1 and other loci on chromosome 17q in human prostate cancer. Cancer Res 1995; 55:1002-1005.
72. Aita VM, Liang XH, Murty VV, et al. Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics 1999; 59:59-65.
73. Liang XH, Jackson S, Seaman M, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999; 402:672-676.
74. Shi YH, Ding ZB, Zhou J, Qiu SJ, Fan J. Prognostic significance of Beclin 1-dependent apoptotic activity in hepatocellular carcinoma. Autophagy 2009; 5:380-382.
75. Koukourakis MI, Giatromanolaki A, Sivridis E, et al. Beclin 1 over- and underexpression in colorectal cancer: distinct patterns relate to prognosis and tumour hypoxia. Br J Cancer 2010; 103:1209-1214.
76. Wan XB, Fan XJ, Chen MY, et al. Elevated Beclin 1 expression is correlated with HIF-1? in predicting poor prognosis of nasopharyngeal carcinoma. Autophagy 2010; 6:395-404.
77. Giatromanolaki A, Koukourakis MI, Koutsopoulos A, et al. High Beclin 1 expression defines a poor prognosis in endometrial adenocarcinomas. Gynecol Oncol 2011; 123:147-151.
78. Xia P, Wang JJ, Zhao BB, Song CL. The role of beclin-1 expression in patients with gastric cancer: a meta-analysis. Tumour Biol 2013 Aug 14; doi:10.1007/s13277-013-1049-8
79. He C, Levine B. The Beclin 1 interactome. Curr Opin Cell Biol 2010; 22:140-149.
80. Ciechomska IA, Goemans GC, Skepper JN, Tolkovsky AM. Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function. Oncogene 2009; 28:2128-2141.
81. Kang R, Zeh HJ, Lotze MT, Tang D. The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ 2011; 18:571-580.
82. Thoresen SB, Pedersen NM, Liestl K, Stenmark H. A phosphatidylinositol 3-kinase class III sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates cytokinesis and degradative endocytic traffic. Exp Cell Res 2010; 316:3368-3378.
83. Ruck A, Attonito J, Garces KT, et al. The Atg6/Vps30/Beclin 1 ortholog BEC-1 mediates endocytic retrograde transport in addition to autophagy in Celegans. Autophagy 2011; 7:386-400.
84. Gentile M, Ahnstrm M, Schn F, Wingren S. Candidate tumour suppressor genes at 11q23-q24 in breast cancer: evidence of alterations in PIG8, a gene involved in p53-induced apoptosis. Oncogene 2001; 20:7753-7760.
85. Zhao X, Ayer RE, Davis SL ei al. Apoptosis factor EI24/ PIG8 is a novel endoplasmic reticulum-localized Bcl-2-binding protein which is associated with suppression of breast cancer invasiveness. Cancer Res 2005; 65:2125-2129.
86. Kim MS, Song SY, Lee JY, Yoo NJ, Lee SH. Expressional and mutational analyses of ATG5 gene in prostate cancers. APMIS 2011; 119:802-807.
87. Liu H, He Z, von Rtte T, et al. Down-regulation of autophagy- related protein 5 (ATG5) contributes to the pathogenesis of early-stage cutaneous melanoma. Sci Transl Med 2013; 5:202ra123.
88. Liang C, Feng P, Ku B, et al. Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nat Cell Biol 2006; 8:688-698.
89. Cheng Y, Ren X, Hait WN, Yang JM. Therapeutic targeting of autophagy in disease: biology and pharmacology. Pharmacol Rev 2013; 65:1162-1197.
90. Hampe J, Franke A, Rosenstiel P, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet 2007; 39:207-211.
91. Rioux JD, Xavier RJ, Taylor KD, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 2007; 39:596-604.
92. Baumgart DC, Sandborn WJ. Crohns disease. Lancet 2012; 380:1590-1605.
93. Mizushima N, Noda T, Ohsumi Y. Apg16p is required for the function of the Apg12p-Apg5p conjugate in the yeast autophagy pathway. EMBO J 1999; 18:3888-3896.
94. Fujioka Y, Noda NN, Nakatogawa H, Ohsumi Y, Inagaki F. Dimeric coiled-coil structure of saccharomyces cerevisiae Atg16 and its functional significance in autophagy. J Biol Chem 2010; 285:1508-1515.
95. Gammoh N, Florey O, Overholtzer M, Jiang X. Interaction between FIP200 and ATG16L1 distinguishes ULK1 complex- dependent and -independent autophagy. Nat Struct Mol Biol 2013; 20:144-149.
96. Nishimura T, Kaizuka T, Cadwell K, et al. FIP200 regulates targeting of Atg16L1 to the isolation membrane. EMBO Rep 2013; 14:284-291.
97. Fujita N, Saitoh T, Kageyama S, Akira S, Noda T, Yoshimori T. Differential involvement of Atg16L1 in Crohn disease and canonical autophagy: analysis of the organization of the Atg16L1 complex in fibroblasts. J Biol Chem 2009; 284:32602-32609.
98. Saitoh T, Fujita N, Jang MH, et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1? production. Nature 2008; 456:264-268.
99. Cadwell K, Liu JY, Brown SL, et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 2008; 456:259-263.
100. Marchiando AM, Ramanan D, Ding Y, et al. A deficiency in the autophagy gene Atg16L1 enhances resistance to enteric bacterial infection. Cell Host Microbe 2013; 14:216-224.
101. Parkes M, Barrett JC, Prescott NJ, et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohns disease susceptibility. Nat Genet 2007; 39:830-832.
102. McCarroll SA, Huett A, Kuballa P, et al. Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohns disease. Nat Genet 2008; 40:1107-1112.
103. Brest P, Lapaquette P, Souidi M, et al. A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohns disease. Nat Genet 2011; 43:242-245.
104. Hampe J, Cuthbert A, Croucher PJ, et al. Association between insertion mutation in NOD2 gene and Crohns disease in German and British populations. Lancet 2001; 357:1925-1928.
105. Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohns disease. Nature 2001; 411:599-603.
106. Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohns disease. Nature 2001; 411:603-606.
107. Stappenbeck TS, Rioux JD, Mizoguchi A, et al. Crohn disease: a current perspective on genetics, autophagy and immunity. Autophagy 2011; 7:355-374.
108. Rubinsztein DC, Codogno P, Levine B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat Rev Drug Discov 2012; 11:709-730.
109. Ravikumar B, Vacher C, Berger Z, et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 2004; 36:585-595.
110. Martinet W, Verheye S, De Meyer GR. Everolimus-induced mTOR inhibition selectively depletes macrophages in atherosclerotic plaques by autophagy. Autophagy 2007; 3:241-244.
111. Lin CI, Whang EE, Donner DB, et al. Autophagy induction with RAD001 enhances chemosensitivity and radiosensitivity through Met inhibition in papillary thyroid cancer. Mol Cancer Res 2010; 8:1217-1226.
112. Mita M, Sankhala K, Abdel-Karim I, Mita A, Giles F. Deforolimus (AP23573) a novel mTOR inhibitor in clinical development. Expert Opin Investig Drugs 2008; 17:1947-1954.
113. Thoreen CC, Kang SA, Chang JW, et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin- resistant functions of mTORC1. J Biol Chem 2009; 284:8023-8032.
114. Feldman ME, Apsel B, Uotila A, et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 2009; 7:e38.
115. Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and ?-synuclein. J Biol Chem 2007; 282:5641-5652.
116. LaRocca TJ, Henson GD, Thorburn A, et al. Translational evidence that impaired autophagy contributes to arterial ageing. J Physiol 2012; 590:3305-3316.
117. Hidvegi T, Ewing M, Hale P, et al. An autophagy-enhancing drug promotes degradation of mutant ?1-antitrypsin and reduces hepatic fibrosis. Science 2010; 329:229-232.
118. Shoji-Kawata S, Sumpter R, Leveno M, et al. Identification of a candidate therapeutic autophagy-inducing peptide. Nature 2013; 494:201-206.
119. Fedorko M. Effect of chloroquine on morphology of cytoplasmic granules in maturing human leukocytes-an ultrastructural study. J Clin Invest 1967; 46:1932-1942.
120. Amaravadi RK, Yu D, Lum JJ, et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 2007; 117:326-336.
121. Amaravadi RK, Lippincott-Schwartz J, Yin XM, et al. Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res 2011; 17:654-666.
122. McAfee Q, Zhang Z, Samanta A, et al. Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency. Proc Natl Acad Sci USA 2012; 109:8253-8258.
123. Seglen PO, Gordon PB. 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc Natl Acad Sci USA 1982; 79:1889-1892.
124. Wu Y, Wang X, Guo H, et al. Synthesis and screening of 3-MA derivatives for autophagy inhibitors. Autophagy 2013; 9:595-603.
125. Miller S, Tavshanjian B, Oleksy A, et al. Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34. Science 2010; 327:1638-1642.
126. Sugawara K, Suzuki NN, Fujioka Y, et al. Structural basis for the specificity and catalysis of human Atg4B responsible for mammalian autophagy. J Biol Chem 2005; 280:40058-40065.
127. Kumanomidou T, Mizushima T, Komatsu M, et al. The crystal structure of human Atg4b, a processing and de-conjugating enzyme for autophagosome-forming modifiers. J Mol Biol 2006; 355:612-618.
128. Noda N, Satoo K, Fujioka Y, et al. Structural basis of Atg8 activation by a homodimeric E1, Atg7. Mol Cell 2011; 44:462-475.
129. Taherbhoy A, Tait S, Kaiser S, et al. Atg8 transfer from Atg7 to Atg3: a distinctive E1-E2 architecture and mechanism in the autophagy pathway. Mol Cell 2011; 44:451-461.
130. Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell 2010; 140:313-326.
131. Kuma A, Matsui M, Mizushima N. LC3, an autophagosome marker, can be incorporated into protein aggregates independent of autophagy: caution in the interpretation of LC3 localization. Autophagy 2007; 3:323-328.
132. Martin LJ, Gupta J, Jyothula SS, et al. Functional variant in the autophagy-related 5 gene promotor is associated with childhood asthma. PLoS One 2012; 7:e33454.
133. Poon A, Eidelman D, Laprise C, Hamid Q. ATG5, autophagy and lung function in asthma. Autophagy 2012; 8:694-695.
134. Zhou XJ, Lu XL, Lv JC, et al. Genetic association of PRDM1- ATG5 intergenic region and autophagy with systemic lupus erythematosus in a Chinese population. Ann Rheum Dis 2011; 70:1330-1337.
135. Pierdominici M, Vomero M, Barbati C, et al. Role of autophagy in immunity and autoimmunity, with a special focus on systemic lupus erythematosus. FASEB J 2012; 26:1400-1412.
136. Barrett JC, Hansoul S, Nicolae DL, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohns disease. Nat Genet 2008; 40:955-962.
137. Zhao YG, Zhao H, Miao L, et al. The p53-induced gene Ei24 is an essential component of the basal autophagy pathway. J Biol Chem 2012; 287:42053-42063.
138. Franke A, Balschun T, Sina C, et al. Genome-wide association study for ulcerative colitis identifies risk loci at 7q22 and 22q13 (IL17REL). Nat Genet 2010; 42:292-294.
139. Laurin N, Brown JP, Morissette J, et al. Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. The Am J Hum Genet 2002; 70:1582-1588.
140. Rubino E, Rainero I, Chi A, et al. SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Neurology 2012; 79:1556-1562.
141. Hirano M, Nakamura Y, Saigoh K, et al. Mutations in the gene encoding p62 in Japanese patients with amyotrophic lateral sclerosis. Neurology 2013; 80:458-463.
142. Martinez-Outschoorn UE, Pavlides S, Whitaker-Menezes D, et al. Tumor cells induce the cancer associated fibroblast phenotype via caveolin-1 degradation: implications for breast cancer and DCIS therapy with autophagy inhibitors. Cell Cycle 2010; 9:2423-2433.
143. Rojas-Puentes L, Gonzalez-Pinedo M, Crismatt A, et al. Phase II randomized, double-blind, placebo-controlled study of whole-brain irradiation with concomitant chloroquine for brain metastases. Radiat Oncol 2013; 8:209.
144. Fornai F, Longone P, Cafaro L, et al. Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 2008; 105:2052-2057.