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The Autophagy Effector Beclin 1: a Novel BH3-Only Protein

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The Autophagy Effector Beclin 1: a Novel BH3-Only Protein Oncogene (2009) 27, S137–S148 & 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09 $32.00 www.nature.com/onc REVIEW The autophagy effector Beclin 1: a novel BH3-only protein S Sinha1 and B Levine2,3,4, 1Department of Chemistry, Biochemistry and Molecular Biology, North Dakota State University, Fargo, ND, USA; 2Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; 3Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA and 4Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA BH3 domains were originally discovered in the context tumor suppression (Levine and Klionsky, 2004; Shintani of apoptosis regulators and they mediate binding of and Klionsky, 2004; Levine and Kroemer, 2008; proapoptotic Bcl-2 family members to antiapoptotic Bcl-2 Mizushima et al., 2008). The disruption of autophagy family members. Yet, recent studies indicate that BH3 has been implicated in a wide variety of diseases inclu- domains do not function uniquely in apoptosis regulation; ding cancer, neurodegenerative disorders, skeletal and they also function in the regulation of another critical cardiac myopathies, cancer, inflammatory bowel disease pathway involved in cellular and tissue homeostasis called and infectious diseases (Levine and Kroemer, 2008). autophagy. Antiapoptotic Bcl-2 homologs downregulate The autophagy pathway is conserved among all autophagy through interactions with the essential auto- eukaryotes, and in the last decade many autophagy phagy effector and haploinsufficient tumor suppressor, effectors (called Atg proteins) as well as major protein Beclin 1. Beclin 1 contains a BH3 domain, similar to that regulators have been identified (Levine and Klionsky, of Bcl-2 proteins, which is necessary and sufficient for 2004; Xie and Klionsky, 2007). Regulators that induce binding to antiapoptotic Bcl-2 homologs and required for autophagy include tumor suppressors, such as PTEN, Bcl-2-mediated inhibition of autophagy. This review will TSC1 and TSC2 complexes, and DAPk; stress-activated summarize the evidence that the BH3 domain of Beclin 1 signaling molecules, such as c-Jun N-terminal kinase 1 serves as a key structural motif that enables Bcl-2 to (JNK1), and those that respond to low energy (for function not only as an antiapoptotic protein, but also as example, AMP kinase) or endoplasmic reticulum (ER) an antiautophagy protein. stress (for example, PERK, eIF2a-kinase and IRE1), Oncogene (2009) 27, S137–S148; doi:10.1038/onc.2009.51 and molecules involved in innate immune signaling, such as toll-like receptors and immunity-related Keywords: Beclin 1; autophagy; BH3-only; apoptosis; GTPases (Escalatine et al., 2009). Proteins that inhibit Bcl-2; tumor suppressor autophagy include oncogenes, such as class I phospha- tidylinositol 3-OH kinase (PI3K), Akt, Ras, TOR and Bcl-2 (Pattingre and Levine, 2006; Maiuri et al., 2008). The tumor suppressor gene, p53, has been reported to Introduction play a dual role in autophagy (Levine and Abrams, 2008; Tasdemir et al., 2008b), with some studies Autophagy is the primary cellular pathway by which suggesting transcription-dependent and transcription- long-lived proteins, cytoplasmic organelles and intracel- independent positive regulation of autophagy (Feng lular pathogens undergo degradation. The pathway et al., 2005; Crighton et al., 2006) and other studies involves sequestration of these cellular constituents in suggesting the negative regulation of autophagy by wild double- or multimembrane cytoplasmic vesicles called type and mutant forms of p53 in the cytoplasm (Morselli autophagosomes, with subsequent delivery to the lyso- et al., 2008; Tasdemir et al., 2008a, 2008c). some, where they are degraded and recycled (Klionsky The molecular structures and mechanism(s) of action and Emr, 2000; Levine and Klionsky, 2004). Autophagy of the autophagy effectors have not been completely promotes cellular survival by enabling cells to maintain elucidated, but most function by participating in multi- macromolecular synthesis and energy homeostasis dur- protein complexes responsible for vesicle induction, ing nutrient deprivation and other forms of cellular nucleation, elongation, docking and fusion with the stress; it also functions in differentiation and develop- lysosome and degradation (Levine and Klionsky, 2004; ment, antiaging, innate and adaptive immunity, and Levine and Kroemer, 2008; Mizushima et al., 2008). Some autophagy regulators induce autophagy through Correspondence: Dr S Sinha, Department of Chemistry, Biochemistry the phosphorylation of key components of the induction and Molecular Biology, North Dakota State University, Fargo, ND, complex, such as Atg1 and Atg13. The process by which USA. targets are selected for autophagy is not understood, E-mail: [email protected] or and may be different for different targets. Autophagy Dr B Levine, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. induction triggers the conversion of phosphatidylinosi- E-mail: [email protected] tol to phosphatidylinositol 3-phosphate (PI3P) by the The autophagy effector Beclin 1 S Sinha and B Levine S138 vesicle nucleation or class III PI3 K complex, and Bif-1, which binds to UVRAG and regulates membrane induces the recruitment of Atg9 and associated curvature (Takahashi et al., 2007), and Ambra1, which mitochondrial lipids to the growing vesicle (He et al., binds to Beclin 1 in a complex containing UVRAG 2008). PI3P serves as a signal to recruit proteins required (Fimia et al., 2007), have each been shown to upregulate for vesicle elongation (Obara and Ohsumi, 2008), the autophagy function of the Beclin 1/class III PI3K which involves two ubiquitin-like conjugation pathways. complex. Thus, additional studies are needed to clarify One pathway results in the conjugation of Atg12 to the role of distinct human Atg14- and UVRAG- Atg5 and the formation of the Atg12–Atg5–Atg16 containing complexes in autophagy and other mem- complex, which then assists in the second pathway, brane trafficking processes. resulting in the conjugation of phosphatidylethanol- Definitive evidence for autophagy-independent amine to Atg8/LC3, and the incorporation of this functions of Beclin 1 in mammalian cells is still lacking, lipidated form of Atg8/LC3 into the growing phago- and two studies showed that Vps34/class III PI3K- phore. The docking and fusion of the completed dependent trafficking events, such as the proteolytic autophagosome with the lysosome is directed by processing of procathepsin D in route from the trans- proteins such as LAMP2 and Rab7, which are also Golgi network to lysosomes or the postendocytic sorting involved in other vesicle trafficking pathways. Ulti- of the epidermal growth factor receptor were intact in mately, the autophagosome, along with its contents, is cells without functional Beclin 1 (Furuya et al., 2005b; degraded by lysosomal hydrolases. The degraded con- Zeng et al., 2006). However, in plants, Ohsumi and tents are recycled by the cell to maintain macromole- colleagues (Fujiki et al., 2007) postulated an autophagy- cular synthesis and energy homeostasis, which is independent function of ATG6/VPS30,asATG6/VPS30 important for survival during nutrient deprivation and mutants, unlike other Arabidopsis thaliana ATG gene other forms of cellular stress. mutants were defective in pollen germination. Further- more, the embryonic phenotype of beclin 1 null mice is more severe than that of other autophagy gene-deficient The essential autophagy effector, Beclin 1 mice (for example, Atg5À/À, Atg7À/À mice; Levine and Kroemer, 2008), suggesting that beclin 1-regulated Beclin 1, initially isolated as a Bcl-2-interacting protein processes other than autophagy may be essential in (Liang et al., 1998), shares 30% sequence identity with early mammalian development. Net, given the presence yeast, Atg6/Vps30, which participates in a protein of distinct Beclin 1/class III PI3K complexes in complex essential for autophagy in yeast (Kametaka mammalian cells, the pleiotropic effects of Beclin 1 et al., 1998). Beclin 1 was among the first mammalian orthologs in lower eukaryotes, and the differences autophagy effectors to be identified and along with the between phenotypes of ATG6 or beclin 1 versus other yeast Vps34 homolog, class III PI3K (Kihara et al., mutant ATG genes in plants and mice, it seems likely 2001), and the yeast Vps15 homolog, p150 (Panaretou that mammalian Beclin 1 also functions in other et al., 1997), forms a complex responsible for autophagic membrane-trafficking processes besides autophagy. vesicle nucleation in mammals (Aita et al., 1999; Liang Despite these possible autophagy-independent func- et al., 1999; Kihara et al., 2001). The precise mechanism tions of Beclin 1, the best-characterized function of Beclin by which the Beclin 1/class III PI3K complex mediates 1 is its role in autophagy. The autophagy function of vesicle nucleation is unclear. Atg6/Beclin 1 is highly conserved throughout eukaryotic The Beclin 1 yeast ortholog, Atg6/Vps30, was also evolution and is presumed to be important in mediating independently discovered in a genetic screen for proteins many of its biological effects. Genetic knockdown or involved in vacuolar protein sorting (Seaman et al., knockout studies of beclin 1, or its orthologs in lower 1997), suggesting that Beclin 1 may also function in eukaryotes have revealed several important phenotypes,
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