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      Autophagy mediates phase transitions from cell death to life

      research-article
      a , b ,   a , *
      Heliyon
      Elsevier
      Autophagy, Mathematical model, Simulations, Phase transitions

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          Abstract

          Autophagy is a lysosomal degradation pathway, which is critical for maintaining normal cellular functions. Despite considerable advances in defining the specific molecular mechanism governing the autophagy pathway during the last decades, we are still far from understanding the underlying principle of the autophagy machinery and its complex role in human disease. As an alternative attempt to reinvigorate the search for the principle of the autophagy pathway, we in this study make use of the computer-aided analysis, complementing current molecular-level studies of autophagy. Specifically, we propose a hypothesis that autophagy mediates cellular phase transitions and demonstrate that the autophagic phase transitions are essential to the maintenance of normal cellular functions and critical in the fate of a cell, i.e., cell death or survival. This study should provide valuable insight into how interactions of sub-cellular components such as genes and protein modules/complexes regulate autophagy and then impact on the dynamic behaviors of living cells as a whole, bridging the microscopic molecular-level studies and the macroscopic cellular-level and physiological approaches.

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          Most cited references30

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          A role for ubiquitin in selective autophagy.

          Ubiquitination is the hallmark of protein degradation by the 26S proteasome. However, the proteasome is limited in its capacity to degrade oligomeric and aggregated proteins. Removal of harmful protein aggregates is mediated by autophagy, a mechanism by which the cell sequesters cytosolic cargo and delivers it for degradation by the lysosome. Identification of autophagy receptors, such as p62/SQSTM1 and NBR1, which simultaneously bind both ubiquitin and autophagy-specific ubiquitin-like modifiers, LC3/GABARAP, has provided a molecular link between ubiquitination and autophagy. This review explores the hypothesis that ubiquitin represents a selective degradation signal suitable for targeting various types of cargo, ranging from protein aggregates to membrane-bound organelles and microbes.
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            Amino acid signalling upstream of mTOR.

            Mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that is part of mTOR complex 1 (mTORC1), a master regulator that couples amino acid availability to cell growth and autophagy. Multiple cues modulate mTORC1 activity, such as growth factors, stress, energy status and amino acids. Although amino acids are key environmental stimuli, exactly how they are sensed and how they activate mTORC1 is not fully understood. Recently, a model has emerged whereby mTORC1 activation occurs at the lysosome and is mediated through an amino acid sensing cascade involving RAG GTPases, Ragulator and vacuolar H(+)-ATPase (v-ATPase).
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              Selective autophagy mediated by autophagic adapter proteins.

              Mounting evidence suggests that autophagy is a more selective process than originally anticipated. The discovery and characterization of autophagic adapters, like p62 and NBR1, has provided mechanistic insight into this process. p62 and NBR1 are both selectively degraded by autophagy and able to act as cargo receptors for degradation of ubiquitinated substrates. A direct interaction between these autophagic adapters and the autophagosomal marker protein LC3, mediated by a so-called LIR (LC3-interacting region) motif, their inherent ability to polymerize or aggregate as well as their ability to specifically recognize substrates are required for efficient selective autophagy. These three required features of autophagic cargo receptors are evolutionarily conserved and also employed in the yeast cytoplasm-to-vacuole targeting (Cvt) pathway and in the degradation of P granules in C. elegans. Here, we review the mechanistic basis of selective autophagy in mammalian cells discussing the degradation of misfolded proteins, p62 bodies, aggresomes, mitochondria and invading bacteria. The emerging picture of selective autophagy affecting the regulation of cell signaling with consequences for oxidative stress responses, tumorigenesis and innate immunity is also addressed.
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                Author and article information

                Contributors
                Journal
                Heliyon
                Heliyon
                Heliyon
                Elsevier
                2405-8440
                26 September 2015
                September 2015
                26 September 2015
                : 1
                : 1
                : e00027
                Affiliations
                [a ]Department of Physics and Astronomy and Center for Theoretical Physics, Seoul National University, Seoul 151-747, South Korea
                [b ]College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, South Korea
                Author notes
                [* ]Corresponding author. Tel.:+82 2 880 6615; fax: +82 2 884 3002. mychoi@ 123456snu.ac.kr
                Article
                S2405-8440(15)30292-9 e00027
                10.1016/j.heliyon.2015.e00027
                4939812
                27441218
                f7c2c552-17e8-4afb-bffb-7f9a2bef59b8
                © 2015 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 31 July 2015
                : 3 September 2015
                : 4 September 2015
                Categories
                Article

                autophagy,mathematical model,simulations,phase transitions

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