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      An ESCRT-LEM protein surveillance system is poised to directly monitor the nuclear envelope and nuclear transport system

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          Abstract

          The integrity of the nuclear membranes coupled to the selective barrier of nuclear pore complexes (NPCs) are essential for the segregation of nucleoplasm and cytoplasm. Mechanical membrane disruption or perturbation to NPC assembly triggers an ESCRT-dependent surveillance system that seals nuclear pores: how these pores are sensed and sealed is ill defined. Using a budding yeast model, we show that the ESCRT Chm7 and the integral inner nuclear membrane (INM) protein Heh1 are spatially segregated by nuclear transport, with Chm7 being actively exported by Xpo1/Crm1. Thus, the exposure of the INM triggers surveillance with Heh1 locally activating Chm7. Sites of Chm7 hyperactivation show fenestrated sheets at the INM and potential membrane delivery at sites of nuclear envelope herniation. Our data suggest that perturbation to the nuclear envelope barrier would lead to local nuclear membrane remodeling to promote membrane sealing. Our findings have implications for disease mechanisms linked to NPC assembly and nuclear envelope integrity.

          eLife digest

          With the exception of bacteria, living cells contain most of their DNA inside a structure called the nucleus. The membranes of the nucleus form a protective wall around the DNA, while pores within this wall act as entry check-points, controlling what can and cannot get inside. Maintaining the structure of this wall is critical for cell survival. Problems can occur if the nuclear wall or its pores become disrupted, as in the case of cancer and neurodegenerative diseases. Thankfully cells have developed a protective surveillance system that can rapidly identify and repair any damage made to the nuclear wall. However, how this damage is found and what activates its repair is poorly understood.

          Now, Thaller et al. have investigated two key proteins that they suspected were involved in the surveillance of the nuclear border in budding yeast: Chm7 and Heh1. Chm7 is part of a complex group of proteins that can cut and sculpt the shape of membranes, while Heh1 is normally embedded on the inside of the nucleus. Thaller et al. discovered that, when the nuclear wall is disrupted, Heh1 recruits Chm7 to the site of damage and activates it. Once activated Chm7 can repair the damage to the nuclear wall, by sealing over defective nuclear pores and closing gaps caused by breakages.

          Thaller et al. showed that the transport system that normally moves molecules into and out of the nucleus also imports Heh1 and actively excludes Chm7, physically segregating them to opposite sides of the nuclear border. If the nuclear wall becomes damaged this leads to the local meeting of Heh1 and Chm7 at these sites. Heh1 will then activate the membrane shaping mechanisms of Chm7, rapidly repairing the nuclear border in response to the damage.

          It is possible cell structures other than the nucleus use a similar surveillance system to protect their borders. Manipulating the border surveillance system of the nucleus could be used to treat the detrimental impacts of damage caused to the nuclear wall by disease.

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          Most cited references 156

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          Fiji: an open-source platform for biological-image analysis.

          Fiji is a distribution of the popular open-source software ImageJ focused on biological-image analysis. Fiji uses modern software engineering practices to combine powerful software libraries with a broad range of scripting languages to enable rapid prototyping of image-processing algorithms. Fiji facilitates the transformation of new algorithms into ImageJ plugins that can be shared with end users through an integrated update system. We propose Fiji as a platform for productive collaboration between computer science and biology research communities.
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            Additional modules for versatile and economical PCR-based gene deletion and modification in Saccharomyces cerevisiae.

            An important recent advance in the functional analysis of Saccharomyces cerevisiae genes is the development of the one-step PCR-mediated technique for deletion and modification of chromosomal genes. This method allows very rapid gene manipulations without requiring plasmid clones of the gene of interest. We describe here a new set of plasmids that serve as templates for the PCR synthesis of fragments that allow a variety of gene modifications. Using as selectable marker the S. cerevisiae TRP1 gene or modules containing the heterologous Schizosaccharomyces pombe his5+ or Escherichia coli kan(r) gene, these plasmids allow gene deletion, gene overexpression (using the regulatable GAL1 promoter), C- or N-terminal protein tagging [with GFP(S65T), GST, or the 3HA or 13Myc epitope], and partial N- or C-terminal deletions (with or without concomitant protein tagging). Because of the modular nature of the plasmids, they allow efficient and economical use of a small number of PCR primers for a wide variety of gene manipulations. Thus, these plasmids should further facilitate the rapid analysis of gene function in S. cerevisiae.
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              Computer visualization of three-dimensional image data using IMOD.

              We have developed a computer software package, IMOD, as a tool for analyzing and viewing three-dimensional biological image data. IMOD is useful for studying and modeling data from tomographic, serial section, and optical section reconstructions. The software allows image data to be visualized by several different methods. Models of the image data can be visualized by volume or contour surface rendering and can yield quantitative information.
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Role: Senior Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                03 April 2019
                2019
                : 8
                Affiliations
                [1 ]deptDepartment of Cell Biology Yale School of Medicine New HavenUnited States
                [2 ]deptStructural and Computational Biology Unit European Molecular Biology Laboratory MeyerhofstrasseGermany
                [3 ]deptElectron Microscopy Core Facility European Molecular Biology Laboratory MeyerhofstrasseGermany
                University of Colorado United States
                The Barcelona Institute of Science and Technology Spain
                University of Colorado United States
                University of Groningen Netherlands
                The Rockefeller University United States
                Article
                45284
                10.7554/eLife.45284
                6461442
                30942170
                © 2019, Thaller et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                Product
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100004410, European Molecular Biology Organization;
                Award ID: Fellowship 6885
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: 5T32GM007223
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100004410, European Molecular Biology Organization;
                Award ID: Fellowship ALTF-1389-2016
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: GM105672
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Cell Biology
                Custom metadata
                ESCRT-driven mechanisms that sense and seal holes in the nuclear membranes directly monitor the nuclear transport system and the exposure of the inner nuclear membrane.

                Life sciences

                escrt, lem2, chmp7, nuclear transport, surveillance, herniation, s. cerevisiae

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