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      Autophagy-activating strategies to promote innate defense against mycobacteria

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          Abstract

          Mycobacterium tuberculosis (Mtb) is a major causal pathogen of human tuberculosis (TB), which is a serious health burden worldwide. The demand for the development of an innovative therapeutic strategy to treat TB is high due to drug-resistant forms of TB. Autophagy is a cell-autonomous host defense mechanism by which intracytoplasmic cargos can be delivered and then destroyed in lysosomes. Previous studies have reported that autophagy-activating agents and small molecules may be beneficial in restricting intracellular Mtb infection, even with multidrug-resistant Mtb strains. Recent studies have revealed the essential roles of host nuclear receptors (NRs) in the activation of the host defense through antibacterial autophagy against Mtb infection. In particular, we discuss the function of estrogen-related receptor (ERR) α and peroxisome proliferator-activated receptor (PPAR) α in autophagy regulation to improve host defenses against Mtb infection. Despite promising findings relating to the antitubercular effects of various agents, our understanding of the molecular mechanism by which autophagy-activating agents suppress intracellular Mtb in vitro and in vivo is lacking. An improved understanding of the antibacterial autophagic mechanisms in the innate host defense will eventually lead to the development of new therapeutic strategies for human TB.

          Tuberculosis: Helping infected cells take out the trash

          Therapies that promote intracellular digestion of microbes could prove a valuable addition to antibiotic weapons against tuberculosis. Mycobacterium tuberculosis (Mtb) establishes itself within immune cells, and employs a variety of tricks to protect itself as it sickens its host. Researchers led by Eun-Kyeong Jo at Chungnam National University, Daejeon, South Korea, have reviewed efforts to defeat this pathogen by jump-starting a cellular ‘recycling’ pathway called autophagy. Autophagy helps cells break down both biomolecules aggregates and potential invaders, but Mtb can elude such digestion. Jo and colleagues highlight antimycobacterial agents that can potentially render Mtb vulnerable to autophagy, as well as promising cellular targets that may allow researchers to access this process. For example, evidence suggests that agents that activate a regulatory protein such as ERRα or PPARα could stimulate cellular degradation of Mtb.

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          Most cited references 101

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          Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).

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            Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages.

            Mycobacterium tuberculosis is an intracellular pathogen persisting within phagosomes through interference with phagolysosome biogenesis. Here we show that stimulation of autophagic pathways in macrophages causes mycobacterial phagosomes to mature into phagolysosomes. Physiological induction of autophagy or its pharmacological stimulation by rapamycin resulted in mycobacterial phagosome colocalization with the autophagy effector LC3, an elongation factor in autophagosome formation. Autophagy stimulation increased phagosomal colocalization with Beclin-1, a subunit of the phosphatidylinositol 3-kinase hVPS34, necessary for autophagy and a target for mycobacterial phagosome maturation arrest. Induction of autophagy suppressed intracellular survival of mycobacteria. IFN-gamma induced autophagy in macrophages, and so did transfection with LRG-47, an effector of IFN-gamma required for antimycobacterial action. These findings demonstrate that autophagic pathways can overcome the trafficking block imposed by M. tuberculosis. Autophagy, which is a hormonally, developmentally, and, as shown here, immunologically regulated process, represents an underappreciated innate defense mechanism for control of intracellular pathogens.
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              Mammalian autophagy: core molecular machinery and signaling regulation.

              Autophagy, a cellular catabolic pathway, is evolutionarily conserved from yeast to mammals. Central to this process is the formation of autophagosomes, double-membrane vesicles responsible for delivering long-lived proteins and excess or damaged organelle into the lysosome for degradation and reuse of the resulting macromolecules. In addition to the hallmark discovery of core molecular machinery components involved in autophagosome formation, complex signaling cascades controlling autophagy have also begun to emerge, with mTOR as a central but far from exclusive player. Malfunction of autophagy has been linked to a wide range of human pathologies, including cancer, neurodegeneration, and pathogen infection. Here we highlight the recent advances in identifying and understanding the core molecular machinery and signaling pathways that are involved in mammalian autophagy. Copyright 2009 Elsevier Ltd. All rights reserved.
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                Author and article information

                Affiliations
                [1 ]ISNI 0000 0001 0722 6377, GRID grid.254230.2, Department of Microbiology, , Chungnam National University School of Medicine, ; Daejeon, 35015 Korea
                [2 ]ISNI 0000 0001 0722 6377, GRID grid.254230.2, Department of Infection Control Convergence Research Center, , Chungnam National University School of Medicine, ; Daejeon, 35015 Korea
                [3 ]ISNI 0000 0000 9149 5707, GRID grid.410885.0, Drug & Disease Target Research Team, Division of Bioconvergence Analysis, , Korea Basic Science Institute (KBSI), ; Cheongju, 28119 South Korea
                [4 ]ISNI 0000 0004 0373 3971, GRID grid.136593.b, Department of Genetics, , Osaka University, ; Osaka, 565-0871 Japan
                [5 ]ISNI 0000 0004 0373 3971, GRID grid.136593.b, Department of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, , Osaka University, ; Osaka, 565-0871 Japan
                [6 ]ISNI 0000 0001 0722 6377, GRID grid.254230.2, Department of Medical Science, , Chungnam National University School of Medicine, ; Daejeon, 35015 Korea
                Contributors
                ORCID: http://orcid.org/0000-0001-7191-0587, +82 42 580 8243 , hayoungj@cnu.ac.kr
                Journal
                Exp Mol Med
                Exp. Mol. Med
                Experimental & Molecular Medicine
                Nature Publishing Group UK (London )
                1226-3613
                2092-6413
                11 December 2019
                11 December 2019
                December 2019
                : 51
                : 12
                290
                10.1038/s12276-019-0290-7
                6906292
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/501100003725, National Research Foundation of Korea (NRF);
                Award ID: 2015K2A2A6002008
                Award ID: 2015K2A2A6002008
                Award Recipient :
                Categories
                Review Article
                Custom metadata
                © The Author(s) 2019

                Molecular medicine

                autophagy, medical research

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