Beclin 1 Biology and its Role in Heart Disease

Author(s): Hongxin Zhu, Lin He Bio-X.

Journal Name: Current Cardiology Reviews

Volume 11 , Issue 3 , 2015

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Graphical Abstract:


Macroautophagy (hereafter termed autophagy) is a highly evolutionarily conserved pathway that degrades intracellular components such as damaged organelles in lysosome. Autophagy occurs at low basal levels in virtually all types of cells, which is required for the maintenance of cellular homeostasis. Beclin 1 protein, encoded by the beclin 1 gene, plays a central role in the regulation of autophagy. Beclin 1 primarily functions as a scaffolding protein assembling Beclin 1 interactome to regulate Class III PI3K/VPS34 activity, which in turn, tightly controls autophagy at multiple stages. In addition to autophagy, Beclin 1 participates in the regulation of other biological processes such as endocytosis, apoptosis and phagocytosis. Fine-tuning of Beclin 1 protein levels, intracellular localization and the assembly of its interactome is pivotal for the proper execution of these biological functions. Deregulation of Beclin 1 contributes to the pathogenesis of a variety of human diseases. In this review, we summarize biology of Beclin 1 and its role in human pathology, with an emphasis on heart disease.

Keywords: Autophagy, Beclin 1, gene expression, heart, microRNA, post-translational modification, protein interaction.

Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science 2000; 290: 1717-21.
Yorimitsu T, Klionsky DJ. Autophagy: molecular machinery for self-eating. Cell Death Differ 2005; 12: 1542-52.
Arroyo DS, Gaviglio EA, Peralta Ramos JM, Bussi C, Rodriguez-Galan MC, Iribarren P. Autophagy in inflammation, infection, neurodegeneration and cancer. Int Immunopharmacol 2014; 18: 55-65.
Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. N Engl J Med 2013; 368: 1845-6.
Klionsky DJ, Cregg JM, Dunn WA Jr, et al. A unified nomenclature for yeast autophagy-related genes. Dev Cell 2003; 5: 539-45.
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.
Fujiki Y, Yoshimoto K, Ohsumi Y. An Arabidopsis homolog of yeast ATG6/VPS30 is essential for pollen germination. Plant Physiol 2007; 143: 1132-9.
Oberstein A, Jeffrey PD, Shi Y. Crystal structure of the Bcl-XL-Beclin 1 peptide complex: Beclin 1 is a novel BH3-only protein. J Biol Chem 2007; 282: 13123-32.
Li X, He L, Che KH, et al. Imperfect interface of Beclin1 coiled-coil domain regulates homodimer and heterodimer formation with Atg14L and UVRAG. Nat Commun 2012; 3: 662.
Furuya N, Yu J, Byfield M, Pattingre S, Levine B. The evolutionarily conserved domain of Beclin 1 is required for Vps34 binding, autophagy and tumor suppressor function. Autophagy 2005; 1: 46-52.
Li X, He L, Che KH, et al. Imperfect interface of Beclin1 coiled-coil domain regulates homodimer and heterodimer formation with Atg14L and UVRAG. Nat Commun 2012; 3: 662.
Huang W, Choi W, Hu W, et al. Crystal structure and biochemical analyses reveal Beclin 1 as a novel membrane binding protein. Cell Res 2012; 22: 473-89.
Noda NN, Kobayashi T, Adachi W, Fujioka Y, Ohsumi Y, Inagaki F. 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 2012; 287: 16256-66.
Kihara A, Kabeya Y, Ohsumi Y, Yoshimori T. Beclin-phosphatidylinositol 3-kinase complex functions at the trans-Golgi network. EMBO Rep 2001; 2: 330-5.
Kang R, Zeh HJ, Lotze MT, Tang D. The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ 2011; 18: 571-80.
He C, Levine B. The Beclin 1 interactome. Curr Opin Cell Biol 2010; 22: 140-9.
Sun Q, Fan W, Chen K, Ding X, Chen S, Zhong Q. Identification of Barkor as a mammalian autophagy-specific factor for Beclin 1 and class III phosphatidylinositol 3-kinase. Proc Natl Acad Sci USA 2008; 105: 19211-6.
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: 5360-72.
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: 688-99.
Takahashi Y, Coppola D, Matsushita N, et al. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol 2007; 9: 1142-51.
Itakura E, Mizushima N. Atg14 and UVRAG: mutually exclusive subunits of mammalian Beclin 1-PI3K complexes. Autophagy 2009; 5: 534-6.
Liang C, Lee JS, Inn KS, et al. Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nat Cell Biol 2008; 10: 776-87.
Zhong Y, Wang QJ, Li X, et al. Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat Cell Biol 2009; 11: 468-76.
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: 385-96.
Liu J, Xia H, Kim M, et al. Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13. Cell 2011; 147: 223-34.
Song Z, An L, Ye Y, et al. Essential role for UVRAG in autophagy and maintenance of cardiac function. Cardiovasc Res 2014; 101: 48-56.
Fimia GM, Stoykova A, Romagnoli A, et al. Ambra1 regulates autophagy and development of the nervous system. Nature 2007; 447: 1121-5.
Xia P, Wang S, Du Y, et al. WASH inhibits autophagy through suppression of Beclin 1 ubiquitination. EMBO J 2013; 32: 2685-96.
Pattingre S, Tassa A, Qu X, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 2005; 122: 927-39.
Maiuri MC, Le Toumelin G, Criollo A, et al. Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J 2007; 26: 2527-39.
Germain M, Nguyen AP, Le Grand JN, et al. MCL-1 is a stress sensor that regulates autophagy in a developmentally regulated manner. EMBO J 2011; 30: 395-407.
Mealer RG, Murray AJ, Shahani N, Subramaniam S, Snyder SH. Rhes, a striatal-selective protein implicated in Huntington disease, binds beclin-1 and activates autophagy. J Biol Chem 2014; 289: 3547-54.
Strappazzon F, Vietri-Rudan M, Campello S, et al. Mitochondrial Bcl-2 inhibits Ambra1-induced autophagy. EMBO J 2011; 30: 1195-208.
Liang XH, Jackson S, Seaman M, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999; 402: 672-6.
Qu X, Yu J, Bhagat G, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 2003; 112: 1809-20.
Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci USA 2003; 100: 15077-82.
Zhou WH, Tang F, Xu J, et al. Low expression of Beclin 1, associated with high Bcl-xL, predicts a malignant phenotype and poor prognosis of gastric cancer. Autophagy 2012; 8: 389-400.
Nicotra G, Mercalli F, Peracchio C, et al. Autophagy-active beclin-1 correlates with favourable clinical outcome in non-Hodgkin lymphomas. Mod Pathol 2010; 23: 937-50.
Fu LL, Cheng Y, Liu B. Beclin-1: autophagic regulator and therapeutic target in cancer. Int J Biochem Cell Biol 2013; 45: 921-4.
Kuma A, Hatano M, Matsui M, et al. The role of autophagy during the early neonatal starvation period. Nature 2004; 432: 1032-6.
Komatsu M, Waguri S, Ueno T, et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 2005; 169: 425-34.
Pickford F, Masliah E, Britschgi M, et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest 2008; 118: 2190-9.
Nascimento-Ferreira I, Nóbrega C, Vasconcelos-Ferreira A, et al. Beclin 1 mitigates motor and neuropathological deficits in genetic mouse models of Machado-Joseph disease. Brain 2013; 136: 2173-88.
Lucin KM, O’Brien CE, Bieri G, et al. Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer’s disease. Neuron 2013; 79: 873-86.
Liang XH, Yu J, Brown K, Levine B. Beclin 1 contains a leucine-rich nuclear export signal that is required for its autophagy and tumor suppressor function. Cancer Res 2001; 61: 3443-9.
Shibata M, Lu T, Furuya T, et al. Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1. J Biol Chem 2006; 281: 14474-85.
Salminen A, Kaarniranta K, Kauppinen A, et al. Impaired autophagy and APP processing in Alzheimer’s disease: The potential role of Beclin 1 interactome. Prog Neurobiol 2013; 106-107: 33-54.
Luo S, Garcia-Arencibia M, Zhao R, et al. Bim inhibits autophagy by recruiting Beclin 1 to microtubules. Mol Cell 2012; 47: 359-70.
Wang RC, Wei Y, An Z, et al. Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science 2012; 338: 956-9.
Nah J, Pyo JO, Jung S, et al. BECN1/Beclin 1 is recruited into lipid rafts by prion to activate autophagy in response to amyloid β 42. Autophagy 2013; 9: 2009-21.
Copetti T, Demarchi F, Schneider C. p65/RelA binds and activates the beclin 1 promoter. Autophagy 2009; 5: 858-9.
Weinmann AS, Bartley SM, Zhang T, Zhang MQ, Farnham PJ. Use of chromatin immunoprecipitation to clone novel E2F target promoters. Mol Cell Biol 2001; 21: 6820-32.
Miao LJ, Huang FX, Sun ZT, Zhang RX, Huang SF, Wang J. Stat3 inhibits Beclin 1 expression through recruitment of HDAC3 in nonsmall cell lung cancer cells. Tumour Biol 2014; 35: 7097-103.
Margariti A, Li H, Chen T, et al. XBP1 mRNA splicing triggers an autophagic response in endothelial cells through BECLIN-1 transcriptional activation. J Biol Chem 2013; 288: 859-72.
Jung KH, Noh JH, Kim JK, et al. Histone deacetylase 6 functions as a tumor suppressor by activating c-Jun NH2-Terminal kinase-mediated Beclin 1-dependent autophagic cell death in liver cancer. Hepatology 2012; 56: 644-57.
Wang J, Whiteman MW, Lian H, et al. Regulating Beclin 1 Pathway Regulates Autophagy via a non-canonical MEK/ERK signaling. J Biol Chem 2009; 284: 21412-24.
Li Z, Chen B, Wu Y, Jin F, Xia Y, Liu X. Genetic and epigenetic silencing of the beclin 1 gene in sporadic breast tumors. BMC Cancer 2010; 10: 98.
Korkmaz G, Tekirdag KA, Ozturk DG, Kosar A, Sezerman OU, Gozuacik D. MIR376A is a regulator of starvation-induced autophagy. PLoS One 2013; 8e82556
Korkmaz G, le Sage C, Tekirdag KA, Agami R, Gozuacik D. miR-376b controls starvation and mTOR inhibition-related autophagy by targeting ATG4C and BECN1. Autophagy 2012; 8: 165-76.
Seca H, Lima RT, Lopes-Rodrigues V, Guimaraes JE, Almeida GM, Vasconcelos MH. Targeting miR-21 induces autophagy and chemosensitivity of leukemia cells. Curr Drug Targets 2013; 14: 1135-43.
Xu X, Fu Y, Tong J, et al. MicroRNA-216b/Beclin 1 axis regulates autophagy and apoptosis in human Tenon’s capsule fibroblasts upon hydroxycamptothecin exposure. Exp Eye Res 2014; 123: 43-55.
Chatterjee A, Chattopadhyay D, Chakrabarti G. miR-17-5p Downregulation Contributes to Paclitaxel Resistance of Lung Cancer Cells through Altering Beclin1 Expression. PLoS One 2014; 9e95716
Xu Q, Meng S, Liu B, et al. MicroRNA-130a regulates autophagy of endothelial progenitor cells through Runx3. Clin Exp Pharmacol Physiol 2014; 41: 351-7.
Wang P, Liang J, Li Y, et al. Down-regulation of miRNA-30a alleviates cerebral ischemic injury through enhancing Beclin 1-mediated autophagy. Neurochem Res 2014; 39: 1279-91.
Zalckvar E, Berissi H, Mizrachy L, et al. DAP-kinase-mediated phosphorylation on the BH3 domain of beclin 1 promotes dissociation of beclin 1 from Bcl-XL and induction of autophagy. EMBO Rep 2009; 10: 285-92.
Russell RC, Tian Y, Yuan H, et al. ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat Cell Biol 2013; 15: 741-50.
Fogel AI, Dlouhy BJ, Wang C, et al. Role of Membrane Association and Atg14-Dependent Phosphorylation in Beclin-1-Mediated Autophagy. Mol Cell Biol 2013; 33: 3675-88.
Wei Y, Zou Z, Becker N, et al. EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell 2013; 154: 1269-84.
Kim J, Kim YC, Fang C, et al. Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell 2013; 152: 290-303.
Platta HW, Abrahamsen H, Thoresen SB, Stenmark H. Nedd4-dependent lysine-11-linked polyubiquitination of the tumour suppressor Beclin 1. Biochem J 2012; 441: 399-406.
Shi CS, Kehrl JH. TRAF6 and A20 regulate lysine 63-linked ubiquitination of Beclin-1 to control TLR4-induced autophagy. Sci Signal 2010; 3: ra42.
Cho DH, Jo YK, Hwang JJ, Lee YM, Roh SA, Kim JC. Caspase-mediated cleavage of ATG6/Beclin-1 links apoptosis to autophagy in HeLa cells. Cancer Lett 2009; 274: 95-100.
Zhu Y, Zhao L, Liu L, et al. Beclin 1 cleavage by caspase-3 inactivates autophagy and promotes apoptosis. Protein Cell 2010; 1: 468-77.
Wirawan E, Vande Walle L, Kersse K, et al. Caspase-mediated cleavage of Beclin-1 inactivates Beclin-1-induced autophagy and enhances apoptosis by promoting the release of proapoptotic factors from mitochondria. Cell Death Dis 2010; 1e18
Rohn TT, Wirawan E, Brown RJ, Harris JR, Masliah E, Vandenabeele P. Depletion of Beclin-1 due to proteolytic cleavage by caspases in the Alzheimer’s disease brain. Neurobiol Dis 2011; 43: 68-78.
Li H, Wang P, Sun Q, et al. Following cytochrome c release, autophagy is inhibited during chemotherapy-induced apoptosis by caspase 8-mediated cleavage of Beclin 1. Cancer Res 2011; 71: 3625-34.
Li H, Wang P, Yu J, Zhang L. Cleaving Beclin 1 to suppress autophagy in chemotherapy-induced apoptosis. Autophagy 2011; 7: 1239-41.
You M, Savaraj N, Kuo MT, et al. TRAIL induces autophagic protein cleavage through caspase activation in melanoma cell lines under arginine deprivation. Mol Cell Biochem 2013; 374: 181-90.
Russo R, Berliocchi L, Adornetto A, et al. Calpain-mediated cleavage of Beclin-1 and autophagy deregulation following retinal ischemic injury in vivo. Cell Death Dis 2011; 2e144
Matsui Y, Takagi H, Qu X, et al. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res 2007; 100: 914-22.
Valentim L, Laurence KM, Townsend PA, et al. Urocortin inhibits Beclin1-mediated autophagic cell death in cardiac myocytes exposed to ischaemia/reperfusion injury. J Mol Cell Cardiol 2006; 40: 846-52.
Ma X, Liu H, Foyil SR, et al. Impaired autophagosome clearance contributes to cardiomyocyte death in ischemia/reperfusion injury. Circulation 2012; 125: 3170-81.
Zeng M, Wei X, Wu Z, et al. NF-κB-mediated induction of autophagy in cardiac ischemia/reperfusion injury. Biochem Biophys Res Commun 2013; 436: 180-5.
Zhu H, Tannous P, Johnstone JL, et al. Cardiac autophagy is a maladaptive response to hemodynamic stress. J Clin Invest 2007; 117: 1782-93.
Lin H, Li H, Chen H, et al. Activating transcription factor 3 protects against pressure-overload heart failure via the autophagy molecule Beclin-1 pathways. Mol Pharmacol 2014; 85: 682-91.
Pan W, Zhong Y, Cheng C, et al. MiR-30-regulated autophagy mediates angiotensin II-induced myocardial hypertrophy. PLoS One 2013; 8e53950
Maejima Y, Kyoi S, Zhai P, et al. Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2. Nat Med 2013; 19: 1478-88.
Anand R, Maksimoska J, Pagano N, et al. Toward the development of a potent and selective organoruthenium mammalian sterile 20 kinase inhibitor. J Med Chem 2009; 52: 1602-11.

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Article Details

Year: 2015
Page: [229 - 237]
Pages: 9
DOI: 10.2174/1573403X10666141106104606
Price: $58

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