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      Systematic mapping of contact sites reveals tethers and a function for the peroxisome-mitochondria contact

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          Abstract

          The understanding that organelles are not floating in the cytosol, but rather held in an organized yet dynamic interplay through membrane contact sites, is altering the way we grasp cell biological phenomena. However, we still have not identified the entire repertoire of contact sites, their tethering molecules and functions. To systematically characterize contact sites and their tethering molecules here we employ a proximity detection method based on split fluorophores and discover four potential new yeast contact sites. We then focus on a little-studied yet highly disease-relevant contact, the Peroxisome-Mitochondria (PerMit) proximity, and uncover and characterize two tether proteins: Fzo1 and Pex34. We genetically expand the PerMit contact site and demonstrate a physiological function in β-oxidation of fatty acids. Our work showcases how systematic analysis of contact site machinery and functions can deepen our understanding of these structures in health and disease.

          Abstract

          The internal organization of the cell has been enriched by the discovery that organelles establish membrane contact sites, however the entire repertoire of these contacts is still being explored. Here the authors systematically identify the landscape of cellular contact sites in yeast, discovering four potential novel contact sites and two tether proteins for the peroxisome-mitochondria contact site.

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          Most cited references51

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          An ER-mitochondria tethering complex revealed by a synthetic biology screen.

          Communication between organelles is an important feature of all eukaryotic cells. To uncover components involved in mitochondria/endoplasmic reticulum (ER) junctions, we screened for mutants that could be complemented by a synthetic protein designed to artificially tether the two organelles. We identified the Mmm1/Mdm10/Mdm12/Mdm34 complex as a molecular tether between ER and mitochondria. The tethering complex was composed of proteins resident of both ER and mitochondria. With the use of genome-wide mapping of genetic interactions, we showed that the components of the tethering complex were functionally connected to phospholipid biosynthesis and calcium-signaling genes. In mutant cells, phospholipid biosynthesis was impaired. The tethering complex localized to discrete foci, suggesting that discrete sites of close apposition between ER and mitochondria facilitate interorganelle calcium and phospholipid exchange.
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            Visualization of interactions among bZIP and Rel family proteins in living cells using bimolecular fluorescence complementation.

            Networks of protein interactions coordinate cellular functions. We describe a bimolecular fluorescence complementation (BiFC) assay for determination of the locations of protein interactions in living cells. This approach is based on complementation between two nonfluorescent fragments of the yellow fluorescent protein (YFP) when they are brought together by interactions between proteins fused to each fragment. BiFC analysis was used to investigate interactions among bZIP and Rel family transcription factors. Regions outside the bZIP domains determined the locations of bZIP protein interactions. The subcellular sites of protein interactions were regulated by signaling. Cross-family interactions between bZIP and Rel proteins affected their subcellular localization and modulated transcription activation. These results attest to the general applicability of the BiFC assay for studies of protein interactions.
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              Mitochondrial-associated endoplasmic reticulum membranes (MAM) form innate immune synapses and are targeted by hepatitis C virus.

              RIG-I is a cytosolic pathogen recognition receptor that engages viral RNA in infected cells to trigger innate immune defenses through its adaptor protein MAVS. MAVS resides on mitochondria and peroxisomes, but how its signaling is coordinated among these organelles has not been defined. Here we show that a major site of MAVS signaling is the mitochondrial-associated membrane (MAM), a distinct membrane compartment that links the endoplasmic reticulum to mitochondria. During RNA virus infection, RIG-I is recruited to the MAM to bind MAVS. Dynamic MAM tethering to mitochondria and peroxisomes then coordinates MAVS localization to form a signaling synapse between membranes. Importantly, the hepatitis C virus NS3/4A protease, which cleaves MAVS to support persistent infection, targets this synapse for MAVS proteolysis from the MAM, but not from mitochondria, to ablate RIG-I signaling of immune defenses. Thus, the MAM mediates an intracellular immune synapse that directs antiviral innate immunity.
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                Author and article information

                Contributors
                maya.schuldiner@weizmann.ac.il
                einat.zalckvar@weizmann.ac.il
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                2 May 2018
                2 May 2018
                2018
                : 9
                : 1761
                Affiliations
                [1 ]ISNI 0000 0004 0604 7563, GRID grid.13992.30, Department of Molecular Genetics, , Weizmann Institute of Science, ; Rehovot, 7610001 Israel
                [2 ]ISNI 0000000084992262, GRID grid.7177.6, Laboratory Genetic Metabolic Diseases, Academic Medical Center, , University of Amsterdam, ; Amsterdam, 1105 AZ The Netherlands
                [3 ]ISNI 0000 0004 0643 538X, GRID grid.450875.b, Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes, , Institut de Biologie Physico-Chimique, Sorbonne Universités, ; UPMC Univ Paris 06, CNRS, UMR8226, 75005 Paris, France
                [4 ]ISNI 0000 0000 8580 3777, GRID grid.6190.e, Institute for Genetics, CECAD Research Center, , University of Cologne, ; 50931 Cologne, Germany
                [5 ]Department of Cell Biology, University of Groningen, University Medical Center Groningen, Amsterdam, The Netherlands
                [6 ]ISNI 0000 0001 2193 0096, GRID grid.223827.e, Department of Biochemistry, , University of Utah School of Medicine, ; Salt Lake City, UT 84112 USA
                Author information
                http://orcid.org/0000-0002-5634-1643
                http://orcid.org/0000-0001-9947-115X
                Article
                3957
                10.1038/s41467-018-03957-8
                5932058
                29720625
                1f2ab55f-8f2d-4456-abfb-7cc529b9b887
                © The Author(s) 2018

                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/.

                History
                : 21 December 2017
                : 22 March 2018
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