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      ESCRT Is a Great Sealer: Non-Endosomal Function of the ESCRT Machinery in Membrane Repair and Autophagy

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      Plant and Cell Physiology
      Oxford University Press (OUP)

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          Abstract

          Components of the endosomal sorting complex required for transport (ESCRTs) were first identified in a genetic screen in budding yeast as factors interfering with vacuolar protein sorting. In the last three decades, intensive studies have revealed the subunit composition of ESCRT-0, ESCRT-I, ESCRT-II, ESCRT-III, their structure, the assembling mechanisms and their molecular and physiological functions. In plants, ESCRTs are essential for development, growth and stress responses. ESCRTs are best known for their function in endosomal trafficking, during which they are required for sorting ubiquitylated membrane proteins into intraluminal vesicles (ILVs) of multivesicular endosomes (MVEs). The formation of ILVs requires the function of ESCRT-III, which has been shown to mediate the membrane scission. Although the function of plant ESCRTs has been predominantly discussed in the context of endosomal trafficking, recent studies in other model organisms revealed a versatile role of ESCRTs in diverse cellular events with broad physiological implications. The non-endosomal functions of ESCRTs include cytokinesis, viral budding, autophagy, nuclear envelope reformation and membrane repair, although many of these have not yet been studied in plants. In this review, recent findings on non-endosomal ESCRT functions in plant, yeast and animals are highlighted and discussed.

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          Most cited references69

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          The many functions of ESCRTs

          Cellular membranes can form two principally different involutions, which either exclude or contain cytosol. The 'classical' budding reactions, such as those occurring during endocytosis or formation of exocytic vesicles, involve proteins that assemble on the cytosol-excluding face of the bud neck. Inverse membrane involution occurs in a wide range of cellular processes, supporting cytokinesis, endosome maturation, autophagy, membrane repair and many other processes. Such inverse membrane remodelling is mediated by a heteromultimeric protein machinery known as endosomal sorting complex required for transport (ESCRT). ESCRT proteins assemble on the cytosolic (or nucleoplasmic) face of the neck of the forming involution and cooperate with the ATPase VPS4 to drive membrane scission or sealing. Here, we review similarities and differences of various ESCRT-dependent processes, with special emphasis on mechanisms of ESCRT recruitment.
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            Nuclear envelope rupture and repair during cancer cell migration.

            During cancer metastasis, tumor cells penetrate tissues through tight interstitial spaces, which requires extensive deformation of the cell and its nucleus. Here, we investigated mammalian tumor cell migration in confining microenvironments in vitro and in vivo. Nuclear deformation caused localized loss of nuclear envelope (NE) integrity, which led to the uncontrolled exchange of nucleo-cytoplasmic content, herniation of chromatin across the NE, and DNA damage. The incidence of NE rupture increased with cell confinement and with depletion of nuclear lamins, NE proteins that structurally support the nucleus. Cells restored NE integrity using components of the endosomal sorting complexes required for transport III (ESCRT III) machinery. Our findings indicate that cell migration incurs substantial physical stress on the NE and its content and requires efficient NE and DNA damage repair for cell survival.
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              ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA damage and cell death.

              In eukaryotic cells, the nuclear envelope separates the genomic DNA from the cytoplasmic space and regulates protein trafficking between the two compartments. This barrier is only transiently dissolved during mitosis. Here, we found that it also opened at high frequency in migrating mammalian cells during interphase, which allowed nuclear proteins to leak out and cytoplasmic proteins to leak in. This transient opening was caused by nuclear deformation and was rapidly repaired in an ESCRT (endosomal sorting complexes required for transport)-dependent manner. DNA double-strand breaks coincided with nuclear envelope opening events. As a consequence, survival of cells migrating through confining environments depended on efficient nuclear envelope and DNA repair machineries. Nuclear envelope opening in migrating leukocytes could have potentially important consequences for normal and pathological immune responses.
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                Author and article information

                Contributors
                Journal
                Plant and Cell Physiology
                Oxford University Press (OUP)
                0032-0781
                1471-9053
                May 01 2021
                October 01 2021
                March 26 2021
                May 01 2021
                October 01 2021
                March 26 2021
                : 62
                : 5
                : 766-774
                Affiliations
                [1 ]Department of Biology, University of Konstanz, Universitätsstrasse 10, Konstanz 78464, Germany
                Article
                10.1093/pcp/pcab045
                33768242
                debfa7a6-4f07-49cf-889a-17956e58754e
                © 2021

                https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

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