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      Post-translational modifications of Beclin 1 provide multiple strategies for autophagy regulation

      , ,
      Cell Death & Differentiation
      Springer Nature

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          Abstract

          Autophagy is a conserved intracellular degradation pathway essential for protein homeostasis, survival and development. Defects in autophagic pathways have been connected to a variety of human diseases, including cancer and neurodegeneration. In the process of macroautophagy, cytoplasmic cargo is enclosed in a double-membrane structure and fused to the lysosome to allow for digestion and recycling of material. Autophagosome formation is primed by the ULK complex, which enables the downstream production of PI(3)P, a key lipid signalling molecule, on the phagophore membrane. The PI(3)P is generated by the PI3 kinase (PI3K) complex, consisting of the core components VPS34, VPS15 and Beclin 1. Beclin 1 is a central player in autophagy and constitutes a molecular platform for the regulation of autophagosome formation and maturation. Post-translational modifications of Beclin 1 affect its stability, interactions and ability to regulate PI3K activity, providing the cell with a plethora of strategies to fine-tune the levels of autophagy. Being such an important regulator, Beclin 1 is a potential target for therapeutic intervention and interfering with the post-translational regulation of Beclin 1 could be one way of manipulating the levels of autophagy. In this review, we provide an overview of the known post-translational modifications of Beclin 1 that govern its role in autophagy and how these modifications are maintained by input from several upstream signalling pathways. ▓.

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          Most cited references63

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          Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor.

          The biochemical properties of beclin 1 suggest a role in two fundamentally important cell biological pathways: autophagy and apoptosis. We show here that beclin 1-/- mutant mice die early in embryogenesis and beclin 1+/- mutant mice suffer from a high incidence of spontaneous tumors. These tumors continue to express wild-type beclin 1 mRNA and protein, establishing that beclin 1 is a haploinsufficient tumor suppressor gene. Beclin 1-/- embryonic stem cells have a severely altered autophagic response, whereas their apoptotic response to serum withdrawal or UV light is normal. These results demonstrate that beclin 1 is a critical component of mammalian autophagy and establish a role for autophagy in tumor suppression. They both provide a biological explanation for recent evidence implicating beclin 1 in human cancer and suggest that mutations in other genes operating in this pathway may contribute to tumor formation through deregulation of autophagy.
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            Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex.

            Beclin 1, a mammalian autophagy protein that has been implicated in development, tumour suppression, neurodegeneration and cell death, exists in a complex with Vps34, the class III phosphatidylinositol-3-kinase (PI(3)K) that mediates multiple vesicle-trafficking processes including endocytosis and autophagy. However, the precise role of the Beclin 1-Vps34 complex in autophagy regulation remains to be elucidated. Combining mouse genetics and biochemistry, we have identified a large in vivo Beclin 1 complex containing the known proteins Vps34, p150/Vps15 and UVRAG, as well as two newly identified proteins, Atg14L (yeast Atg14-like) and Rubicon (RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein). Characterization of the new proteins revealed that Atg14L enhances Vps34 lipid kinase activity and upregulates autophagy, whereas Rubicon reduces Vps34 activity and downregulates autophagy. We show that Beclin 1 and Atg14L synergistically promote the formation of double-membraned organelles that are associated with Atg5 and Atg12, whereas forced expression of Rubicon results in aberrant late endosomal/lysosomal structures and impaired autophagosome maturation. We hypothesize that by forming distinct protein complexes, Beclin 1 and its binding proteins orchestrate the precise function of the class III PI(3)K in regulating autophagy at multiple steps.
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              Regulation of mTORC1 by amino acids.

              The mechanistic target of rapamycin complex I (mTORC1) is a central regulator of cellular and organismal growth, and hyperactivation of this pathway is implicated in the pathogenesis of many human diseases including cancer and diabetes. mTORC1 promotes growth in response to the availability of nutrients, such as amino acids, which drive mTORC1 to the lysosomal surface, its site of activation. How amino acid levels are communicated to mTORC1 is only recently coming to light by the discovery of a lysosome-based signaling system composed of Rags (Ras-related GTPases) and Ragulator v-ATPase, GATOR (GAP activity towards Rags), and folliculin (FLCN) complexes. Increased understanding of this pathway will not only provide insight into growth control but also into the human pathologies triggered by its deregulation. Copyright © 2014 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Cell Death & Differentiation
                Cell Death Differ
                Springer Nature
                1350-9047
                1476-5403
                December 13 2018
                Article
                10.1038/s41418-018-0254-9
                6460389
                30546075
                c2a48050-f7eb-4c69-8e3f-350a9f5f0446
                © 2018

                http://www.springer.com/tdm

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