Identification of Barkor as a mammalian autophagy-specific factor for Beclin 1 and class III phosphatidylinositol 3-kinase

Sun, Qiming; Fan, Weiliang; Chen, Keling; Ding, Xiaojun; Chen, She; Zhong, Qing

doi:10.1073/pnas.0810452105

Cited by 457 publications

(468 citation statements)

References 28 publications

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“…It has been implicated as a critical regulator for a number of molecular and cellular events including endocytic trafficking, autophagy, and mTOR signaling. Its versatile molecular function has been attributed to its various binding partners and distinct subcellular localizations (31)(32)(33). Its importance is exemplified by the fact that germ-line loss of Vps34 leads to embryonic lethality (10).…”

Section: Discussionmentioning

confidence: 99%

Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function

Jaber¹,

Dou²,

Chen³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

329

308

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A critical regulator of autophagy is the Class III PI3K Vps34 (also called PIK3C3). Although Vps34 is known to play an essential role in autophagy in yeast, its role in mammals remains elusive. To elucidate the physiological function of Vps34 and to determine its precise role in autophagy, we have generated Vps34 f/f mice, in which expression of Cre recombinase results in a deletion of exon 4 of Vps34 and a frame shift causing a deletion of 755 of the 887 amino acids of Vps34. Acute ablation of Vps34 in MEFs upon adenoviral Cre infection results in a diminishment of localized generation of phosphatidylinositol 3-phosphate and blockade of both endocytic and autophagic degradation. Starvation-induced autophagosome formation is blocked in both Vps34-null MEFs and liver. Liver-specific Albumin-Cre;Vps34 f/f mice developed hepatomegaly and hepatic steatosis, and impaired protein turnover. Ablation of Vps34 in the heart of muscle creatine kinase-Cre;Vps34 f/f mice led to cardiomegaly and decreased contractility. In addition, while amino acid-stimulated mTOR activation was suppressed in the absence of Vps34, the steady-state level of mTOR signaling was not affected in Vps34-null MEFs, liver, or cardiomyocytes. Taken together, our results indicate that Vps34 plays an essential role in regulating functional autophagy and is indispensable for normal liver and heart function.LC3 | SQSTM1/p62 | 3-MA | epidermal growth factor receptor | transferrin M acroautophagy (referred to as autophagy hereafter) is a dynamic membrane trafficking process that involves the delivery of intracellular content to lysosomes for degradation. A fully executed autophagy includes the formation of doublemembraned autophagosomes, the fusion of autophagosomes to late endosomes/lysosomes, and the digestion of the enclosed content by lysosomal hydrolases. Autophagy is constantly maintained at the basal level and is up-regulated in response to stress conditions, such as nutrient and energy limitation, hypoxia, and DNA damage. Autophagy is necessary for cellular and tissue homeostasis, by eliminating damaged organelles and misfolded proteins, and its dysregulation is implicated in developmental defects and numerous diseases (1-5).

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Section: Discussionmentioning

confidence: 99%

Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function

Jaber¹,

Dou²,

Chen³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

329

308

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“…In contrast, Beclin 1 is required for the interaction between Vps34 and Atg14L. 37 Loss of Beclin 1 or Vps34 greatly reduces Atg14L protein levels, suggesting that these proteins have some nonautophagic functions or altered stability in the absence of forming a complex with Beclin 1/Vps34. Interestingly, PI3K activity is required for starvation-induced Atg5 and ATG16L punctae formation, but not for Atg14L punctae, suggesting that precursor structures of Atg14L form independent of Vps34 and Beclin 1 (Itakura et al 28 ).…”

Section: Other Beclin 1-binding Proteins In Autophagymentioning

confidence: 99%

“…Atg14L, also known as Barkor, 37 contains two CCD that are required for binding the CCD regions of Beclin 1 and Vps34. Atg14L shares an 18% sequence identity and a 32% sequence similarity with yeast Atg14.…”

Section: Other Beclin 1-binding Proteins In Autophagymentioning

confidence: 99%

The Beclin 1 network regulates autophagy and apoptosis

et al. 2011

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Beclin 1, the mammalian orthologue of yeast Atg6, has a central role in autophagy, a process of programmed cell survival, which is increased during periods of cell stress and extinguished during the cell cycle. It interacts with several cofactors (Atg14L, UVRAG, Bif-1, Rubicon, Ambra1, HMGB1, nPIST, VMP1, SLAM, IP 3 R, PINK and survivin) to regulate the lipid kinase Vps-34 protein and promote formation of Beclin 1-Vps34-Vps15 core complexes, thereby inducing autophagy. In contrast, the BH3 domain of Beclin 1 is bound to, and inhibited by Bcl-2 or Bcl-XL. This interaction can be disrupted by phosphorylation of Bcl-2 and Beclin 1, or ubiquitination of Beclin 1. Interestingly, caspase-mediated cleavage of Beclin 1 promotes crosstalk between apoptosis and autophagy. Beclin 1 dysfunction has been implicated in many disorders, including cancer and neurodegeneration. Here, we summarize new findings regarding the organization and function of the Beclin 1 network in cellular homeostasis, focusing on the cross-regulation between apoptosis and autophagy. Cell Death and Differentiation (2011) 18, 571-580; doi:10.1038/cdd.2010 published online 11 February 2011 Autophagy is an essential process that consists of selective degradation of cellular components. There are at least three different types of autophagy described and possibly more. These autophagy types include macroautophagy (hereafter referred to as autophagy), microautophagy and chaperonemediated autophagy. 1 The initial step of autophagy is the surrounding and sequestering of cytoplasmic organelles and proteins within an isolation membrane (phagophore). Potential sources for the membrane to generate the phagophore include the Golgi complex, endosomes, the endoplasmic reticulum (ER), mitochondria and the plasma membrane. 2 The nascent membranes are fused at their edges to form double-membrane vesicles, called autophagosomes. Autophagosomes undergo a stepwise maturation process, including fusion with acidified endosomal and/or lysosomal vesicles, eventually leading to the delivery of cytoplasmic contents to lysosomal components, where they fuse, then degrade and are recycled (Figure 1a). The process of mammalian autophagy is divided into six principal steps: initiation (Figure 1b It has been well demonstrated that autophagy depends on Atg5/Atg7, is associated with microtubule-associated protein light chain 3 (LC3) truncation and lipidation, and may originate directly from the ER membrane and other membrane organelles. Furthermore, recent study has identified a Atg5/Atg7-independent pathway of autophagy. 3 This pathway of autophagy was not associated with LC3 processing but appeared to involve autophagosome formation from late endosomes and the trans-Golgi. 3 Atg7-independent autophagy had been implicated in mitochondrial clearance from reticulocytes. 4 The exact molecular basis of Atg5/Atg7-independent autophagy remains to be elucidated. Interestingly, Beclin 1 is required for Atg5/Atg7-dependent and -independent autophagy. 3 However, the presence of Beclin 1-indep...

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“…This complex consists of class-III PI3K or hVps34 (hereafter referred to as hVps34), its regulatory protein kinase p150 or hVps15, Beclin 1 (Atg6 in yeast), and the recently discovered mammalian homolog of Atg14, known as Atg14L or Barkor (Beclin 1-associated ATG key regulator) [23,24]. The activity of this complex is tightly controlled by positive and negative regulators (see below).…”

Section: Autophagosome Initiationmentioning

confidence: 99%

Overview of macroautophagy regulation in mammalian cells

et al. 2010

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Macroautophagy is a multistep, vacuolar, degradation pathway terminating in the lysosomal compartment, and it is of fundamental importance in tissue homeostasis. In this review, we consider macroautophagy in the light of recent advances in our understanding of the formation of autophagosomes, which are double-membrane-bound vacuoles that sequester cytoplasmic cargos and deliver them to lysosomes. In most cases, this final step is preceded by a maturation step during which autophagosomes interact with the endocytic pathway. The discovery of AuTophaGyrelated genes has greatly increased our knowledge about the mechanism responsible for autophagosome formation, and there has also been progress in the understanding of molecular aspects of autophagosome maturation. Finally, the regulation of autophagy is now better understood because of the discovery that the activity of Atg complexes is targeted by protein kinases, and owing to the importance of nuclear regulation via transcription factors in regulating the expression of autophagy genes.

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Identification of Barkor as a mammalian autophagy-specific factor for Beclin 1 and class III phosphatidylinositol 3-kinase

Cited by 457 publications

References 28 publications

Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function

Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function

The Beclin 1 network regulates autophagy and apoptosis

Overview of macroautophagy regulation in mammalian cells

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