Beclin 1-Vps34 complex architecture: Understanding the nuts and bolts of therapeutic targets

Frontiers in Biology - Tập 10 - Trang 398-426 - 2015
Deanna H. Morris1, Calvin K. Yip2, Yi Shi3, Brian T. Chait3, Qing Jun Wang1,4,5
1Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, USA
2Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, Canada
3Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, USA
4Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, USA
5Markey Cancer Center, University of Kentucky, Lexington, USA

Tóm tắt

Autophagy is an important lysosomal degradation pathway that aids in the maintenance of cellular homeostasis by breaking down and recycling intracellular contents. Dysregulation of autophagy is linked to a growing number of human diseases. The Beclin 1-Vps34 protein-protein interaction network is critical for autophagy regulation and is therefore essential to cellular integrity. Manipulation of autophagy, in particular via modulation of the action of the Beclin 1-Vps34 complexes, is considered a promising route to combat autophagy-related diseases. Here we summarize recent findings on the core components and structural architecture of the Beclin 1-Vps34 complexes, and how these findings provide valuable insights into the molecular mechanisms that underlie the multiple functions of these complexes and for devising therapeutic strategies.

Tài liệu tham khảo

Aita V M, Liang X H, Murty V V, Pincus D L, Yu W, Cayanis E, Kalachikov S, Gilliam T C, Levine B (1999). Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics, 59(1): 59–65 Araki Y, Ku W C, Akioka M, May A I, Hayashi Y, Arisaka F, Ishihama Y, Ohsumi Y (2013). Atg38 is required for autophagy-specific phosphatidylinositol 3-kinase complex integrity. J Cell Biol, 203(2): 299–313 Arena G, Gelmetti V, Torosantucci L, Vignone D, Lamorte G, De Rosa P, Cilia E, Jonas E A, Valente E M (2013). PINK1 protects against cell death induced by mitochondrial depolarization, by phosphorylating Bcl-xL and impairing its pro-apoptotic cleavage. Cell Death Differ, 20(7): 920–930 Arroyo D S, Gaviglio E A, Peralta Ramos J M, Bussi C, Rodriguez- Galan M C, Iribarren P (2014). Autophagy in inflammation, infection, neurodegeneration and cancer. Int Immunopharmacol, 18 (1): 55–65 Arsov I, Adebayo A, Kucerova-Levisohn M, Haye J, MacNeil M, Papavasiliou F N, Yue Z, Ortiz B D (2011). A role for autophagic protein beclin 1 early in lymphocyte development. J Immunol, 186 (4): 2201–2209 Arsov I, Li X, Matthews G, Coradin J, Hartmann B, Simon A K, Sealfon S C, Yue Z (2008). BAC-mediated transgenic expression of fluorescent autophagic protein Beclin 1 reveals a role for Beclin 1 in lymphocyte development. Cell Death Differ, 15(9): 1385–1395 Axe E L, Walker S A, Manifava M, Chandra P, Roderick H L, Habermann A, Griffiths G, Ktistakis N T (2008). Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol, 182(4): 685–701 Backer JM (2008). The regulation and function of Class III PI3Ks: novel roles for Vps34. Biochem J, 410(1): 1–17 Bago R, Malik N, Munson M J, Prescott A R, Davies P, Sommer E, Shpiro N, Ward R, Cross D, Ganley I G, Alessi D R (2014). Characterization of VPS34-IN1, a selective inhibitor of Vps34, reveals that the phosphatidylinositol 3-phosphate-binding SGK3 protein kinase is a downstream target of class III phosphoinositide 3- kinase. Biochem J, 463(3): 413–427 Bai L, Wang S (2014). Targeting apoptosis pathways for new cancer therapeutics. Annu Rev Med, 65(1): 139–155 Baskaran S, Carlson L A, Stjepanovic G, Young L N, Kim D J, Grob P, Stanley R E, Nogales E, Hurley J H (2015). Architecture and dynamics of the autophagic phosphatidylinositol 3-kinase complex. eLife, 3: e05115 Behrends C, Sowa M E, Gygi S P, Harper J W (2010). Network organization of the human autophagy system. Nature, 466(7302): 68–76 Bergamini E, Cavallini G, Donati A, Gori Z (2007). The role of autophagy in aging: its essential part in the anti-aging mechanism of caloric restriction. Ann N Y Acad Sci, 1114(1): 69–78 Blommaart E F, Krause U, Schellens J P, Vreeling-Sindelárová H, Meijer A J (1997). The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. Eur J Biochem, 243(1–2): 240–246 Bodemann B O, Orvedahl A, Cheng T, Ram R R, Ou Y H, Formstecher E, Maiti M, Hazelett C C, Wauson E M, Balakireva M, Camonis J H, Yeaman C, Levine B, White M A (2011). RalB and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly. Cell, 144(2): 253–267 Brunk U T, Terman A (2002). The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis. Eur J Biochem, 269(8): 1996–2002 Budovskaya Y V, Hama H, DeWald D B, Herman P K (2002). The C terminus of the Vps34p phosphoinositide 3-kinase is necessary and sufficient for the interaction with the Vps15p protein kinase. J Biol Chem, 277(1): 287–294 Burgess M R, Skaggs B J, Shah N P, Lee F Y, Sawyers C L (2005). Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance. Proc Natl Acad Sci USA, 102(9): 3395–3400 Byfield M P, Murray J T, Backer J M (2005). hVps34 is a nutrientregulated lipid kinase required for activation of p70 S6 kinase. J Biol Chem, 280(38): 33076–33082 Cao C, Backer J M, Laporte J, Bedrick E J, Wandinger-Ness A (2008). Sequential actions of myotubularin lipid phosphatases regulate endosomal PI(3)P and growth factor receptor trafficking. Mol Biol Cell, 19(8): 3334–3346 Cao C, Laporte J, Backer J M, Wandinger-Ness A, Stein M P (2007). Myotubularin lipid phosphatase binds the hVPS15/hVPS34 lipid kinase complex on endosomes. Traffic, 8(8): 1052–1067 Cao Y, Wang Y, Abi Saab W F, Yang F, Pessin J E, Backer J M (2014). NRBF2 regulates macroautophagy as a component of Vps34 Complex I. BiochemJ, 461(2): 315–322 Chew L H, Yip C K (2014). Structural biology of the macroautophagy machinery. Frontiers in Biology, 9(1): 18–34 Choi A M, Ryter S W, Levine B (2013). Autophagy in human health and disease. N Engl J Med, 368(7): 651–662 Choubey V, Cagalinec M, Liiv J, Safiulina D, Hickey M A, Kuum M, Liiv M, Anwar T, Eskelinen E L, Kaasik A (2014). BECN1 is involved in the initiation of mitophagy: it facilitates PARK2 translocation to mitochondria. Autophagy, 10(6): 1105–1119 Christoforidis S, Miaczynska M, Ashman K, Wilm M, Zhao L, Yip S C, Waterfield M D, Backer J M, Zerial M (1999). Phosphatidylinositol-3-OH kinases are Rab5 effectors. Nat Cell Biol, 1(4): 249–252 Ciccarelli F D, Proukakis C, Patel H, Cross H, Azam S, Patton M A, Bork P, Crosby A H (2003). The identification of a conserved domain in both spartin and spastin, mutated in hereditary spastic paraplegia. Genomics, 81(4): 437–441 Cuervo A M (2008). Calorie restriction and aging: the ultimate “cleansing diet”. J Gerontol A Biol Sci Med Sci, 63(6): 547–549 Darabi H, McCue K, Beesley J, Michailidou K, Nord S, Kar S, Humphreys K, Thompson D, Ghoussaini M, Bolla M K, Dennis J, Wang Q, Canisius S, Scott C G, Apicella C, Hopper J L, Southey M C, Stone J, Broeks A, Schmidt M K, Scott R J, Lophatananon A, Muir K, Beckmann M W, Ekici A B, Fasching P A, Heusinger K, Dos-Santos-Silva I, Peto J, Tomlinson I, Sawyer E J, Burwinkel B, Marme F, Guánel P, Truong T, Bojesen S E, Flyger H, Benitez J, González-Neira A, Anton-Culver H, Neuhausen S L, Arndt V, Brenner H, Engel C, Meindl A, Schmutzler R K, Arnold N, Brauch H, Hamann U, Chang-Claude J, Khan S, Nevanlinna H, Ito H, Matsuo K, Bogdanova N V, Dárk T, Lindblom A, Margolin S, Kosma V M, Mannermaa A, Tseng C C, Wu A H, Floris G, Lambrechts D, Rudolph A, Peterlongo P, Radice P, Couch F J, Vachon C, Giles G G, McLean C, Milne R L, Dugué P A, Haiman C A, Maskarinec G, Woolcott C, Henderson B E, Goldberg M S, Simard J, Teo S H, Mariapun S, Helland Å, Haakensen V, Zheng W, Beeghly-Fadiel A, Tamimi R, Jukkola-Vuorinen A, Winqvist R, Andrulis I L, Knight J A, Devilee P, Tollenaar R A, Figueroa J, García-Closas M, Czene K, Hooning M J, Tilanus-Linthorst M, Li J, Gao Y T, Shu X O, Cox A, Cross S S, Luben R, Khaw K T, Choi J Y, Kang D, Hartman M, Lim W Y, Kabisch M, Torres D, Jakubowska A, Lubinski J, McKay J, Sangrajrang S, Toland A E, Yannoukakos D, Shen C Y, Yu J C, Ziogas A, Schoemaker M J, Swerdlow A, Borresen-Dale A L, Kristensen V, French J D, Edwards S L, Dunning A M, Easton D F, Hall P, Chenevix-Trench G, and the German Consortium of Hereditary Breast and Ovarian Cancer, and the kConFab/AOCS Investigators (2015). Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression. Am J Hum Genet, 97(1): 22–34 Diao J, Liu R, Rong Y, Zhao M, Zhang J, Lai Y, Zhou Q, Wilz L M, Li J, Vivona S, Pfuetzner R A, Brunger A T, Zhong Q (2015). ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. Nature, 520(7548): 563–566 Dooley H C, Razi M, Polson H E, Girardin S E, Wilson M I, Tooze S A (2014). WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1. Mol Cell, 55(2): 238–252 Dou Z, Chattopadhyay M, Pan J A, Guerriero J L, Jiang Y P, Ballou L M, Yue Z, Lin R Z, Zong W X (2010). The class IA phosphatidylinositol 3-kinase p110-beta subunit is a positive regulator of autophagy. J Cell Biol, 191(4): 827–843 Dou Z, Pan J A, Dbouk H A, Ballou L M, DeLeon J L, Fan Y, Chen J S, Liang Z, Li G, Backer J M, Lin R Z, Zong W X (2013). Class IA PI3K p110ß subunit promotes autophagy through Rab5 small GTPase in response to growth factor limitation. Mol Cell, 50(1): 29–42 Dowdle W E, Nyfeler B, Nagel J, Elling R A, Liu S, Triantafellow E, Menon S, Wang Z, Honda A, Pardee G, Cantwell J, Luu C, Cornella-Taracido I, Harrington E, Fekkes P, Lei H, Fang Q, Digan M E, Burdick D, Powers A F, Helliwell S B, D’Aquin S, Bastien J, Wang H, Wiederschain D, Kuerth J, Bergman P, Schwalb D, Thomas J, Ugwonali S, Harbinski F, Tallarico J, Wilson C J, Myer V E, Porter J A, Bussiere D E, Finan P M, Labow M A, Mao X, Hamann L G, Manning B D, Valdez R A, Nicholson T, Schirle M, Knapp M S, Keaney E P, Murphy L O (2014). Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. Nat Cell Biol, 16(11): 1069–1079 Druker B J, Tamura S, Buchdunger E, Ohno S, Segal G M, Fanning S, Zimmermann J, Lydon N B (1996). Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med, 2(5): 561–566 Fan W, Nassiri A, Zhong Q (2011). Autophagosome targeting and membrane curvature sensing by Barkor/Atg14(L). Proc Natl Acad Sci USA, 108(19): 7769–7774 Feng W, Huang S, Wu H, Zhang M (2007). Molecular basis of Bcl-xL’s target recognition versatility revealed by the structure of Bcl-xL in complex with the BH3 domain of Beclin-1. J Mol Biol, 372(1): 223–235 Fimia G M, Stoykova A, Romagnoli A, Giunta L, Di Bartolomeo S, Nardacci R, Corazzari M, Fuoco C, Ucar A, Schwartz P, Gruss P, Piacentini M, Chowdhury K, Cecconi F (2007). Ambra1 regulates autophagy and development of the nervous system. Nature, 447 (7148): 1121–1125 Flores A M, Li L, Aneskievich B J (2004). Isolation and functional analysis of a keratinocyte-derived, ligand-regulated nuclear receptor comodulator. J Invest Dermatol, 123(6): 1092–1101 Fogel A I, Dlouhy B J, Wang C, Ryu S W, Neutzner A, Hasson S A, Sideris D P, Abeliovich H, Youle R J (2013). Role of membrane association and Atg14-dependent phosphorylation in beclin-1-mediated autophagy. Mol Cell Biol, 33(18): 3675–3688 Furuya N, Yu J, Byfield M, Pattingre S, Levine B (2005). The evolutionarily conserved domain of Beclin 1 is required for Vps34 binding, autophagy and tumor suppressor function. Autophagy, 1(1): 46–52 Gannagé M, Dormann D, Albrecht R, Dengjel J, Torossi T, Rämer P C, Lee M, Strowig T, Arrey F, Conenello G, Pypaert M, Andersen J, García-Sastre A, Münz C (2009). Matrix protein 2 of influenza A virus blocks autophagosome fusion with lysosomes. Cell Host Microbe, 6(4): 367–380 Gulati P, Gaspers L D, Dann S G, Joaquin M, Nobukuni T, Natt F, Kozma S C, Thomas A P, Thomas G (2008). Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34. Cell Metab, 7 (5): 456–465 Hamasaki M, Furuta N, Matsuda A, Nezu A, Yamamoto A, Fujita N, Oomori H, Noda T, Haraguchi T, Hiraoka Y, Amano A, Yoshimori T (2013). Autophagosomes form at ER-mitochondria contact sites. Nature, 495(7441): 389–393 Harrison D E, Strong R, Sharp Z D, Nelson J F, Astle C M, Flurkey K, Nadon N L, Wilkinson J E, Frenkel K, Carter C S, Pahor M, JavorsM A, Fernandez E, Miller R A (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature, 460 (7253): 392–395 Heenan E J, Vanhooke J L, Temple B R, Betts L, Sondek J E, Dohlman H G (2009). Structure and function of Vps15 in the endosomal G protein signaling pathway. Biochemistry, 48(27): 6390–6401 Herman P K, Emr S D (1990). Characterization of VPS34, a gene required for vacuolar protein sorting and vacuole segregation in Saccharomyces cerevisiae. Mol Cell Biol, 10(12): 6742–6754 Herman P K, Stack J H, DeModena J A, Emr S D (1991a). A novel protein kinase homolog essential for protein sorting to the yeast lysosome-like vacuole. Cell, 64(2): 425–437 Herman P K, Stack J H, Emr S D (1991b). A genetic and structural analysis of the yeast Vps15 protein kinase: evidence for a direct role of Vps15p in vacuolar protein delivery. EMBO J, 10(13): 4049–4060 Huang W, Choi W, Hu W, Mi N, Guo Q, Ma M, Liu M, Tian Y, Lu P, Wang F L, Deng H, Liu L, Gao N, Yu L, Shi Y (2012). Crystal structure and biochemical analyses reveal Beclin 1 as a novel membrane binding protein. Cell Res, 22(3): 473–489 Hurley J H, Schulman B A (2014). Atomistic autophagy: the structures of cellular self-digestion. Cell, 157(2): 300–311 Itakura E, Kishi C, Inoue K, Mizushima N (2008). Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell, 19(12): 5360–5372 Itakura E, Kishi-Itakura C, Mizushima N (2012). The hairpin-type tailanchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell, 151(6): 1256–1269 Itakura E, Mizushima N (2010). Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins. Autophagy, 6(6): 764–776 Jaber N, Dou Z, Chen J S, Catanzaro J, Jiang Y P, Ballou L M, Selinger E, Ouyang X, Lin R Z, Zhang J, Zong W X (2012). Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function. Proc Natl Acad Sci USA, 109(6): 2003–2008 Jaeger P A, Pickford F, Sun C H, Lucin K M, Masliah E, Wyss-Coray T (2010). Regulation of amyloid precursor protein processing by the Beclin 1 complex. PLoS ONE, 5(6): e11102 Joffre C, Dupont N, Hoa L, Gomez V, Pardo R, Gonçalves-Pimentel C, Achard P, Bettoun A, Meunier B, Bauvy C, Cascone I, Codogno P, Fanto M, Hergovich A, Camonis J (2015). The Pro-apoptotic STK38 Kinase Is a New Beclin1 Partner Positively Regulating Autophagy. Curr Biol Kametaka S, Okano T, Ohsumi M, Ohsumi Y (1998). Apg14p and Apg6/Vps30p form a protein complex essential for autophagy in the yeast, Saccharomyces cerevisiae. J Biol Chem, 273(35): 22284–22291 Karsli-Uzunbas G, Guo J Y, Price S, Teng X, Laddha S V, Khor S, Kalaany N Y, Jacks T, Chan C S, Rabinowitz J D, White E (2014). Autophagy is required for glucose homeostasis and lung tumor maintenance. Cancer Discov, 4(8): 914–927 Kieffer C, Skalicky J J, Morita E, De Domenico I, Ward D M, Kaplan J, Sundquist W I (2008). Two distinct modes of ESCRT-III recognition are required for VPS4 functions in lysosomal protein targeting and HIV-1 budding. Dev Cell, 15(1): 62–73 Kihara A, Kabeya Y, Ohsumi Y, Yoshimori T (2001). Beclinphosphatidylinositol 3-kinase complex functions at the trans-Golgi network. EMBO Rep, 2(4): 330–335 Kihara A, Noda T, Ishihara N, Ohsumi Y (2001). Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J Cell Biol, 152(3): 519–530 Kim J, Kim Y C, Fang C, Russell R C, Kim J H, Fan W, Liu R, Zhong Q, Guan K L (2013). Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell, 152(1-2): 290–303 Kim M S, Jeong E G, Ahn C H, Kim S S, Lee S H, Yoo N J (2008). Frameshift mutation of UVRAG, an autophagy-related gene, in gastric carcinomas with microsatellite instability. Hum Pathol, 39(7): 1059–1063 Kim Y M, Jung C H, Seo M, Kim E K, Park J M, Bae S S, Kim D H (2015). mTORC1 phosphorylates UVRAG to negatively regulate autophagosome and endosome maturation. Mol Cell, 57(2): 207–218 Ku B, Woo J S, Liang C, Lee K H, Hong H S, e X, Kim K S, Jung J U, Oh B H (2008). Structural and biochemical bases for the inhibition of autophagy and apoptosis by viral BCL-2 of murine gammaherpesvirus 68. PLoS Pathog, 4(2): e25 Kudchodkar S B, Levine B (2009). Viruses and autophagy. Rev Med Virol, 19(6): 359–378 Kunz J B, Schwarz H, Mayer A (2004). Determination of four sequential stages during microautophagy in vitro. J Biol Chem, 279(11): 9987–9996 Kyei G B, Dinkins C, Davis A S, Roberts E, Singh S B, Dong C, Wu L, Kominami E, Ueno T, Yamamoto A, Federico M, Panganiban A, Vergne I, Deretic V (2009). Autophagy pathway intersects with HIV-1 biosynthesis and regulates viral yields in macrophages. J Cell Biol, 186(2): 255–268 Laddha S V, Ganesan S, Chan C S, White E (2014). Mutational landscape of the essential autophagy gene BECN1 in human cancers. Mol Cancer Res, 12(4): 485–490 Levine B, Mizushima N, Virgin H W (2011). Autophagy in immunity and inflammation. Nature, 469(7330): 323–335 Li X, He L, Che K H, Funderburk S F, Pan L, Pan N, Zhang M, Yue Z, Zhao Y (2012). Imperfect interface of Beclin1 coiled-coil domain regulates homodimer and heterodimer formation with Atg14L and UVRAG. Nat Commun, 3: 662 Liang C, Feng P, Ku B, Dotan I, Canaani D, Oh B H, Jung J U (2006). Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nat Cell Biol, 8(7): 688–699 Liang C, Lee J S, Inn K S, Gack M U, Li Q, Roberts E A, Vergne I, Deretic V, Feng P, Akazawa C, Jung J U (2008). Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nat Cell Biol, 10(7): 776–787 Liang Q, Chang B, Brulois K F, Castro K, Min C K, Rodgers M A, Shi M, Ge J, Feng P, Oh B H, Jung J U (2013). Kaposi’s sarcomaassociated herpesvirus K7 modulates Rubicon-mediated inhibition of autophagosome maturation. J Virol, 87(22): 12499–12503 Liang Q, Seo G J, Choi Y J, Kwak M J, Ge J, Rodgers M A, Shi M, Leslie B J, Hopfner K P, Ha T, Oh B H, Jung J U (2014). Crosstalk between the cGAS DNA sensor and Beclin-1 autophagy protein shapes innate antimicrobial immune responses. Cell Host Microbe, 15(2): 228–238 Liang X H, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B (1999). Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature, 402(6762): 672–676 Liang X H, Kleeman L K, Jiang H H, Gordon G, Goldman J E, Berry G, Herman B, Levine B (1998). Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol, 72 (11): 8586–8596 Lindmo K, Brech A, Finley K D, Gaumer S, Contamine D, Rusten T E, Stenmark H (2008). The PI 3-kinase regulator Vps15 is required for autophagic clearance of protein aggregates. Autophagy, 4(4): 500–506 Liu J, Xia H, Kim M, Xu L, Li Y, Zhang L, Cai Y, Norberg H V, Zhang T, Furuya T, Jin M, Zhu Z, Wang H, Yu J, Li Y, Hao Y, Choi A, Ke H, Ma D, Yuan J (2011). Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13. Cell, 147(1): 223–234 Lu J, He L, Behrends C, Araki M, Araki K, JunWang Q, Catanzaro J M, Friedman S L, Zong W X, Fiel M I, Li M, Yue Z (2014). NRBF2 regulates autophagy and prevents liver injury by modulating Atg14Llinked phosphatidylinositol-3 kinase III activity. Nat Commun, 5: 3920–3934 Lucin K M, O’ Brien C E, Bieri G, Czirr E, Mosher K I, Abbey R J, Mastroeni D F, Rogers J, Spencer B, Masliah E, Wyss-Coray T (2013). Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer’s disease. Neuron, 79 (5): 873–886 Ma B, Cao W, Li W, Gao C, Qi Z, Zhao Y, Du J, Xue H, Peng J, Wen J, Chen H, Ning Y, Huang L, Zhang H, Gao X, Yu L, Chen Y G (2014). Dapper1 promotes autophagy by enhancing the Beclin1-Vps34- Atg14L complex formation. Cell Res, 24(8): 912–924 Maiuri M C, Criollo A, Tasdemir E, Vicencio J M, Tajeddine N, Hickman J A, Geneste O, Kroemer G (2007). BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-X(L). Autophagy, 3(4): 374–376 Maiuri M C, Le Toumelin G, Criollo A, Rain J C, Gautier F, Juin P, Tasdemir E, Pierron G, Troulinaki K, Tavernarakis N, Hickman J A, Geneste O, Kroemer G (2007). Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J, 26 (10): 2527–2539 Martell R E, Brooks D G, Wang Y, Wilcoxen K (2013). Discovery of novel drugs for promising targets. Clin Ther, 35(9): 1271–1281 Massey A C, Kaushik S, Cuervo A M (2006). Lysosomal chat maintains the balance. Autophagy, 2(4): 325–327 Mathew R, White E (2011). Autophagy in tumorigenesis and energy metabolism: friend by day, foe by night. Curr Opin Genet Dev, 21(1): 113–119 Matsunaga K, Morita E, Saitoh T, Akira S, Ktistakis N T, Izumi T, Noda T, Yoshimori T (2010). Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L. J Cell Biol, 190(4): 511–521 Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N, Maejima I, Shirahama-Noda K, Ichimura T, Isobe T, Akira S, Noda T, Yoshimori T (2009). Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol, 11(4): 385–396 McKnight N C, Jefferies H B, Alemu E A, Saunders R E, Howell M, Johansen T, Tooze S A (2012). Genome-wide siRNA screen reveals amino acid starvation-induced autophagy requires SCOC and WAC. EMBO J, 31(8): 1931–1946 McKnight N C, Zhong Y,WoldMS, Gong S, Phillips G R, Dou Z, Zhao Y, Heintz N, Zong W X, Yue Z (2014). Beclin 1 is required for neuron viability and regulates endosome pathways via the UVRAGVPS34 complex. PLoS Genet, 10(10): e1004626 Meléndez A, Tallóczy Z, Seaman M, Eskelinen E L, Hall D H, Levine B (2003). Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science, 301(5638): 1387–1391 Michnick S W, Ear P H, Manderson E N, Remy I, Stefan E (2007). Universal strategies in research and drug discovery based on proteinfragment complementation assays. Nat Rev Drug Discov, 6(7): 569–582 Miller S, Tavshanjian B, Oleksy A, Perisic O, Houseman B T, Shokat K M, Williams R L (2010). Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34. Science, 327 (5973): 1638–1642 Mizushima N, Yoshimori T, Ohsumi Y (2011). The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol, 27(1): 107–132 Molejon M I, Ropolo A, Re A L, Boggio V, Vaccaro M I (2013). The VMP1-Beclin 1 interaction regulates autophagy induction. Sci Rep, 3: 1055 Munson MJ, Allen G F, Toth R, Campbell D G, Lucocq J M, Ganley I G (2015). mTOR activates the VPS34-UVRAG complex to regulate autolysosomal tubulation and cell survival. EMBO J, 34(17): 2272–2290 Münz C (2011). Beclin-1 targeting for viral immune escape. Viruses, 3 (7): 1166–1178 Murray J T, Panaretou C, Stenmark H, Miaczynska M, Backer J M (2002). Role of Rab5 in the recruitment of hVps34/p150 to the early endosome. Traffic, 3(6): 416–427 Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y (2009). Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol, 10(7): 458–467 Nassif M, Valenzuela V, Rojas-Rivera D, Vidal R, Matus S, Castillo K, Fuentealba Y, Kroemer G, Levine B, Hetz C (2014). Pathogenic role of BECN1/Beclin 1 in the development of amyotrophic lateral sclerosis. Autophagy, 10(7): 1256–1271 Nazio F, Strappazzon F, Antonioli M, Bielli P, Cianfanelli V, Bordi M, Gretzmeier C, Dengjel J, Piacentini M, Fimia G M, Cecconi F (2013). mTOR inhibits autophagy by controlling ULK1 ubiquitylation, selfassociation and function through AMBRA1 and TRAF6. Nat Cell Biol, 15(4): 406–416 Nemazanyy I, Montagnac G, Russell R C, Morzyglod L, Burnol A F, Guan K L, Pende M, Panasyuk G (2015). Class III PI3K regulates organismal glucose homeostasis by providing negative feedback on hepatic insulin signalling. Nat Commun, 6: 8283 Noble C G, Dong J M, Manser E, Song H (2008). Bcl-xL and UVRAG cause a monomer-dimer switch in Beclin1. J Biol Chem, 283(38): 26274–26282 Nobukuni T, Joaquin M, Roccio M, Dann S G, Kim S Y, Gulati P, Byfield M P, Backer J M, Natt F, Bos J L, Zwartkruis F J, Thomas G (2005). Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc Natl Acad Sci USA, 102(40): 14238–14243 Noda N N, Kobayashi T, Adachi W, Fujioka Y, Ohsumi Y, Inagaki F (2012). Structure of the novel C-terminal domain of vacuolar protein sorting 30/autophagy-related protein 6 and its specific role in autophagy. J Biol Chem, 287(20): 16256–16266 Oberstein A, Jeffrey P D, Shi Y (2007). Crystal structure of the Bcl-XLBeclin 1 peptide complex: Beclin 1 is a novel BH3-only protein. J Biol Chem, 282(17): 13123–13132 Obita T, Saksena S, Ghazi-Tabatabai S, Gill D J, Perisic O, Emr S D, Williams R L (2007). Structural basis for selective recognition of ESCRT-III by the AAA ATPase Vps4. Nature, 449(7163): 735–739 Orvedahl A, Alexander D, Tallóczy Z, Sun Q, Wei Y, Zhang W, Burns D, Leib D A, Levine B (2007). HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host Microbe, 1(1): 23–35 Panaretou C, Domin J, Cockcroft S, Waterfield M D (1997). Characterization of p150, an adaptor protein for the human phosphatidylinositol (PtdIns) 3-kinase. Substrate presentation by phosphatidylinositol transfer protein to the p150. Ptdins 3-kinase complex. J Biol Chem, 272(4): 2477–2485 Pankiv S, Alemu E A, Brech A, Bruun J A, Lamark T, Overvatn A, Bjørkøy G, Johansen T (2010). FYCO1 is a Rab7 effector that binds to LC3 and PI3P to mediate microtubule plus end-directed vesicle transport. J Cell Biol, 188(2): 253–269 Pasquier B, El-Ahmad Y, Filoche-Rommé B, Dureuil C, Fassy F, Abecassis P Y, Mathieu M, Bertrand T, Benard T, Barrière C, El Batti S, Letallec J P, Sonnefraud V, Brollo M, Delbarre L, Loyau V, Pilorge F, Bertin L, Richepin P, Arigon J, Labrosse J R, Clément J, Durand F, Combet R, Perraut P, Leroy V, Gay F, Lefrançois D, Bretin F, Marquette J P, Michot N, Caron A, Castell C, Schio L, McCort G, Goulaouic H, Garcia-Echeverria C, Ronan B (2015). Discovery of (2S)-8-((3R)-3-methylmorpholin-4-yl)-1-(3-methyl-2- oxobutyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyrimido(1,2-a)pyrimidin- 6-one: a novel potent and selective inhibitor of Vps34 for the treatment of solid tumors. J Med Chem, 58(1): 376–400 Pattingre S, Tassa A, Qu X, Garuti R, Liang X H, Mizushima N, Packer M, Schneider M D, Levine B (2005). Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell, 122(6): 927–939 Phillips S A, Barr V A, Haft D H, Taylor S I, Haft C R (2001). Identification and characterization of SNX15, a novel sorting nexin involved in protein trafficking. J Biol Chem, 276(7): 5074–5084 Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger P A, Small S, Spencer B, Rockenstein E, Levine B, Wyss-Coray T (2008). The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest, 118(6): 2190–2199 Polson H E, de Lartigue J, Rigden D J, Reedijk M, Urbé S, Clague M J, Tooze S A (2010). Mammalian Atg18 (WIPI2) localizes to omegasome-anchored phagophores and positively regulates LC3 lipidation. Autophagy, 6(4): 506–522 Powis G, Bonjouklian R, Berggren M M, Gallegos A, Abraham R, Ashendel C, Zalkow L, Matter W F, Dodge J, Grindey G, et al (1994). Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Res, 54(9): 2419–2423 Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen E L, Mizushima N, Ohsumi Y, Cattoretti G, Levine B (2003). Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest, 112(12): 1809–1820 Ravikumar B, Imarisio S, Sarkar S, O’Kane C J, Rubinsztein D C (2008). Rab5 modulates aggregation and toxicity of mutant huntingtin through macroautophagy in cell and fly models of Huntington disease. J Cell Sci, 121(Pt 10): 1649–1660 Ronan B, Flamand O, Vescovi L, Dureuil C, Durand L, Fassy F, Bachelot M F, Lamberton A, Mathieu M, Bertrand T, Marquette J P, El-Ahmad Y, Filoche-Romme B, Schio L, Garcia-Echeverria C, Goulaouic H, Pasquier B (2014). A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nat Chem Biol, 10(12): 1013–1019 Ropolo A, Grasso D, Pardo R, Sacchetti M L, Archange C, Lo Re A, Seux M, Nowak J, Gonzalez C D, Iovanna J L, Vaccaro M I (2007). The pancreatitis-induced vacuole membrane protein 1 triggers autophagy in mammalian cells. J Biol Chem, 282(51): 37124–37133 Rostislavleva K, Soler N, Ohashi Y, Zhang L, Pardon E, Burke J E, Masson G R, Johnson C, Steyaert J, Ktistakis N T, Williams R L (2015). Structure and flexibility of the endosomal Vps34 complex reveals the basis of its function on membranes. Science, 350: aac7365 Schu P V, Takegawa K, Fry M J, Stack J H, Waterfield M D, Emr S D (1993). Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting. Science, 260(5104): 88–91 Seglen P O, Gordon P B (1982). 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc Natl Acad Sci USA, 79(6): 1889–1892 Shah N P, Tran C, Lee F Y, Chen P, Norris D, Sawyers C L (2004). Overriding imatinib resistance with a novel ABL kinase inhibitor. Science, 305(5682): 399–401 Shi Y, Pellarin R, Fridy P C, Fernandez-Martinez J, Thompson M K, Li Y, Wang Q J, Sali A, Rout M P, Chait B T (2015). A strategy for dissecting the architectures of native macromolecular assemblies. Nature Methods, doi: 10.1038/nmeth.3617 Shibata M, Lu T, Furuya T, Degterev A, Mizushima N, Yoshimori T, MacDonald M, Yankner B, Yuan J (2006). Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1. J Biol Chem, 281 (20): 14474–14485 Shoji-Kawata S, Sumpter R, Leveno M, Campbell G R, Zou Z, Kinch L, Wilkins A D, Sun Q, Pallauf K, MacDuff D, Huerta C, Virgin H W, Helms J B, Eerland R, Tooze S A, Xavier R, Lenschow D J, Yamamoto A, King D, Lichtarge O, Grishin N V, Spector S A, Kaloyanova D V, Levine B (2013). Identification of a candidate therapeutic autophagy-inducing peptide. Nature, 494(7436): 201–206 Siddhanta U, McIlroy J, Shah A, Zhang Y, Backer J M (1998). Distinct roles for the p110alpha and hVPS34 phosphatidylinositol 3'-kinases in vesicular trafficking, regulation of the actin cytoskeleton, and mitogenesis. J Cell Biol, 143(6): 1647–1659 Simonsen A, Birkeland H C, Gillooly D J, Mizushima N, Kuma A, Yoshimori T, Slagsvold T, Brech A, Stenmark H (2004). Alfy, a novel FYVE-domain-containing protein associated with protein granules and autophagic membranes. J Cell Sci, 117(Pt 18): 4239–4251 Sinha S, Colbert C L, Becker N, Wei Y, Levine B (2008). Molecular basis of the regulation of Beclin 1-dependent autophagy by the gamma-herpesvirus 68 Bcl-2 homolog M11. Autophagy, 4(8): 989–997 Slessareva J E, Routt S M, Temple B, Bankaitis V A, Dohlman H G (2006). Activation of the phosphatidylinositol 3-kinase Vps34 by a G protein alpha subunit at the endosome. Cell, 126(1): 191–203 Spencer B, Potkar R, Trejo M, Rockenstein E, Patrick C, Gindi R, Adame A, Wyss-Coray T, Masliah E (2009). Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson’s and Lewy body diseases. J Neurosci, 29(43): 13578–13588 Stack J H, DeWald D B, Takegawa K, Emr S D (1995). Vesicle-mediated protein transport: regulatory interactions between the Vps15 protein kinase and the Vps34 PtdIns 3-kinase essential for protein sorting to the vacuole in yeast. J Cell Biol, 129(2): 321–334 Stack J H, Herman P K, Schu P V, Emr S D (1993). A membraneassociated complex containing the Vps15 protein kinase and the Vps34 PI 3-kinase is essential for protein sorting to the yeast lysosome-like vacuole. EMBO J, 12(5): 2195–2204 Starr T, Child R, Wehrly T D, Hansen B, Hwang S, López-Otin C, Virgin H W, Celli J (2012). Selective subversion of autophagy complexes facilitates completion of the Brucella intracellular cycle. Cell Host Microbe, 11(1): 33–45 Strappazzon F, Nazio F, Corrado M, Cianfanelli V, Romagnoli A, Fimia G M, Campello S, Nardacci R, Piacentini M, Campanella M, Cecconi F (2014). AMBRA1 is able to induce mitophagy via LC3 binding, regardless of PARKIN and p62/SQSTM1. Cell Death Differ Strappazzon F, Vietri-Rudan M, Campello S, Nazio F, Florenzano F, Fimia G M, Piacentini M, Levine B, Cecconi F (2011). Mitochondrial BCL-2 inhibits AMBRA1-induced autophagy. EMBO J, 30(7): 1195–1208 Stuchell-Brereton M D, Skalicky J J, Kieffer C, Karren M A, Ghaffarian S, Sundquist W I (2007). ESCRT-III recognition by VPS4 ATPases. Nature, 449(7163): 740–744 Su M, Mei Y, Sanishvili R, Levine B, Colbert C L, Sinha S (2014). Targeting γ-herpesvirus 68 Bcl-2-mediated down-regulation of autophagy. J Biol Chem, 289(12): 8029–8040 Sun Q, Fan W, Chen K, Ding X, Chen S, Zhong Q (2008). Identification of Barkor as a mammalian autophagy-specific factor for Beclin 1 and class III phosphatidylinositol 3-kinase. Proc Natl Acad Sci USA, 105 (49): 19211–19216 Sun Q, Westphal W, Wong K N, Tan I, Zhong Q (2010). Rubicon controls endosome maturation as a Rab7 effector. Proc Natl Acad Sci USA, 107(45): 19338–19343 Sun Q, Zhang J, Fan W, Wong K N, Ding X, Chen S, Zhong Q (2011). The RUN domain of rubicon is important for hVps34 binding, lipid kinase inhibition, and autophagy suppression. J Biol Chem, 286(1): 185–191 Suetake T, Hayashi F, Yokoyama S (2015). Solution structure of MIT domain from mouse Nrbf2. (To be published) Suzuki K, Ohsumi Y (2007). Molecular machinery of autophagosome formation in yeast, Saccharomyces cerevisiae. FEBS Lett, 581(11): 2156–2161 Taguchi-Atarashi N, Hamasaki M, Matsunaga K, Omori H, Ktistakis N T, Yoshimori T, Noda T (2010). Modulation of local PtdIns3P levels by the PI phosphatase MTMR3 regulates constitutive autophagy. Traffic, 11(4): 468–478 Takahashi Y, Coppola D, Matsushita N, Cualing H D, Sun M, Sato Y, Liang C, Jung J U, Cheng J Q, Mulé J J, Pledger W J, Wang H G (2007). Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol, 9(10): 1142–1151 Takamura A, Komatsu M, Hara T, Sakamoto A, Kishi C, Waguri S, Eishi Y, Hino O, Tanaka K, Mizushima N (2011). Autophagy-deficient mice develop multiple liver tumors. Genes Dev, 25(8): 795–800 Takáts S, Pircs K, Nagy P, Varga Á, Kárpáti M, Hegedus K, Kramer H, Kovács A L, Sass M, Juhász G (2014). Interaction of the HOPS complex with Syntaxin 17 mediates autophagosome clearance in Drosophila. Mol Biol Cell, 25(8): 1338–1354 Terman A (1995). The effect of age on formation and elimination of autophagic vacuoles in mouse hepatocytes. Gerontology, 41(Suppl 2): 319–326 Terman A, Gustafsson B, Brunk U T (2006). The lysosomalmitochondrial axis theory of postmitotic aging and cell death. Chem Biol Interact, 163(1–2): 29–37 Thoresen S B, Pedersen N M, Liestøl K, Stenmark H (2010). 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, 316(20): 3368–3378 Uttenweiler A, Schwarz H, Neumann H, Mayer A (2007). The vacuolar transporter chaperone (VTC) complex is required for microautophagy. Mol Biol Cell, 18(1): 166–175 Vakser I A (2014). Protein-protein docking: from interaction to interactome. Biophys J, 107(8): 1785–1793 Van Humbeeck C, Cornelissen T, Hofkens H, Mandemakers W, Gevaert K, De Strooper B, Vandenberghe W (2011). Parkin interacts with Ambra1 to induce mitophagy. J Neurosci, 31(28): 10249–10261 Vergne I, Roberts E, Elmaoued R A, Tosch V, Delgado M A, Proikas-Cezanne T, Laporte J, Deretic V (2009). Control of autophagy initiation by phosphoinositide 3-phosphatase Jumpy. EMBO J, 28 (15): 2244–2258 Vlahos C J, Matter W F, Hui K Y, Brown R F (1994). A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8- phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem, 269(7): 5241–5248 Volinia S, Dhand R, Vanhaesebroeck B, MacDougall L K, Stein R, Zvelebil M J, Domin J, Panaretou C, Waterfield M D (1995). A human phosphatidylinositol 3-kinase complex related to the yeast Vps34p-Vps15p protein sorting system. EMBO J, 14(14): 3339–3348 Wei Y, Pattingre S, Sinha S, Bassik M, Levine B (2008). JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell, 30(6): 678–688 Wei Y, Zou Z, Becker N, Anderson M, Sumpter R, Xiao G, Kinch L, Koduru P, Christudass C S, Veltri R W, Grishin N V, Peyton M, Minna J, Bhagat G, Levine B (2013). EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell, 154(6): 1269–1284 Wu Y T, Tan H L, Shui G, Bauvy C, Huang Q, Wenk M R, Ong C N, Codogno P, Shen H M (2010). Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase. J Biol Chem, 285(14): 10850–10861 Xu L, Salloum D, Medlin P S, Saqcena M, Yellen P, Perrella B, Foster D A (2011). Phospholipase D mediates nutrient input to mammalian target of rapamycin complex 1 (mTORC1). J Biol Chem, 286(29): 25477–25486 Yan Y, Flinn R J, Wu H, Schnur R S, Backer J M (2009). hVps15, but not Ca2+/CaM, is required for the activity and regulation of hVps34 in mammalian cells. Biochem J, 417(3): 747–755 Yang C S, Lee J S, Rodgers M, Min C K, Lee J Y, Kim H J, Lee K H, Kim C J, Oh B, Zandi E, Yue Z, Kramnik I, Liang C, Jung J U (2012a). Autophagy protein Rubicon mediates phagocytic NADPH oxidase activation in response to microbial infection or TLR stimulation. Cell Host Microbe, 11(3): 264–276 Yang C S, Rodgers M, Min C K, Lee J S, Kingeter L, Lee J Y, Jong A, Kramnik I, Lin X, Jung J U (2012b). The autophagy regulator Rubicon is a feedback inhibitor of CARD9-mediated host innate immunity. Cell Host Microbe, 11(3): 277–289 Yasumo H, Masuda N, Furusawa T, Tsukamoto T, Sadano H, Osumi T (2000). Nuclear receptor binding factor-2 (NRBF-2), a possible gene activator protein interacting with nuclear hormone receptors. Biochim Biophys Acta, 1490(1–2): 189–197 Yoon M S, Du G, Backer J M, Frohman M A, Chen J (2011). Class III PI-3-kinase activates phospholipase D in an amino acid-sensing mTORC1 pathway. J Cell Biol, 195(3): 435–447 Yue Z, Jin S, Yang C, Levine A J, Heintz N (2003). Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci USA, 100 (25): 15077–15082 Zalckvar E, Berissi H, Mizrachy L, Idelchuk Y, Koren I, Eisenstein M, Sabanay H, Pinkas-Kramarski R, Kimchi A (2009). DAP-kinasemediated phosphorylation on the BH3 domain of beclin 1 promotes dissociation of beclin 1 from Bcl-XL and induction of autophagy. EMBO Rep, 10(3): 285–292 Zhong Y, Morris D H, Jin L, Patel M S, Karunakaran S K, Fu Y J, Matuszak E A, Weiss H L, Chait B T, Wang Q J (2014). Nrbf2 protein suppresses autophagy by modulating Atg14L proteincontaining Beclin 1-Vps34 complex architecture and reducing intracellular phosphatidylinositol-3 phosphate levels. J Biol Chem, 289(38): 26021–26037 Zhong Y, Wang Q J, Li X, Yan Y, Backer J M, Chait B T, Heintz N, Yue Z (2009). Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat Cell Biol, 11(4): 468–476 Zhou D, Spector S A (2008). Human immunodeficiency virus type-1 infection inhibits autophagy. AIDS, 22(6): 695–699 Zhou X, Takatoh J, Wang F (2011). The mammalian class 3 PI3K (PIK3C3) is required for early embryogenesis and cell proliferation. PLoS ONE, 6(1): e16358