Blog
About

26
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Autophagy mediates degradation of nuclear lamina

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Macroautophagy (hereafter referred to as autophagy) is a catabolic membrane trafficking process that degrades a variety of cellular constituents, and is associated with human diseases 13 . While extensive studies have focused on autophagic turnover of cytoplasmic materials, little is known regarding the role of autophagy in degrading nuclear components. Here we report that the autophagy machinery mediates degradation of nuclear lamina components in mammals. The autophagy protein LC3/Atg8, which is involved in autophagy membrane trafficking and substrate delivery 46 , is present in the nucleus and directly interacts with the nuclear lamina protein Lamin B1, and binds to lamin-associated domains (LADs) on chromatin. This LC3-Lamin B1 interaction does not downregulate Lamin B1 during starvation, but mediates its degradation upon oncogenic insults, such as by activated Ras. Lamin B1 degradation is achieved by nucleus-to-cytoplasm transport that delivers Lamin B1 to the lysosome. Inhibiting autophagy or the LC3-Lamin B1 interaction prevents activated Ras-induced Lamin B1 loss and attenuates oncogene-induced senescence in primary human cells. Our study suggests this new function of autophagy as a guarding mechanism protecting cells from tumorigenesis.

          Related collections

          Most cited references 18

          • Record: found
          • Abstract: found
          • Article: not found

          The role of Atg proteins in autophagosome formation.

          Macroautophagy is mediated by a unique organelle, the autophagosome, which encloses a portion of cytoplasm for delivery to the lysosome. Autophagosome formation is dynamically regulated by starvation and other stresses and involves complicated membrane reorganization. Since the discovery of yeast Atg-related proteins, autophagosome formation has been dissected at the molecular level. In this review we describe the molecular mechanism of autophagosome formation with particular focus on the function of Atg proteins and the long-standing discussion regarding the origin of the autophagosome membrane.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a.

            Oncogenic ras can transform most immortal rodent cells to a tumorigenic state. However, transformation of primary cells by ras requires either a cooperating oncogene or the inactivation of tumor suppressors such as p53 or p16. Here we show that expression of oncogenic ras in primary human or rodent cells results in a permanent G1 arrest. The arrest induced by ras is accompanied by accumulation of p53 and p16, and is phenotypically indistinguishable from cellular senescence. Inactivation of either p53 or p16 prevents ras-induced arrest in rodent cells, and E1A achieves a similar effect in human cells. These observations suggest that the onset of cellular senescence does not simply reflect the accumulation of cell divisions, but can be prematurely activated in response to an oncogenic stimulus. Negation of ras-induced senescence may be relevant during multistep tumorigenesis.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              A role for NBR1 in autophagosomal degradation of ubiquitinated substrates.

              Autophagy is a catabolic process where cytosolic cellular components are delivered to the lysosome for degradation. Recent studies have indicated the existence of specific receptors, such as p62, which link ubiquitinated targets to autophagosomal degradation pathways. Here we show that NBR1 (neighbor of BRCA1 gene 1) is an autophagy receptor containing LC3- and ubiquitin (Ub)-binding domains. NBR1 is recruited to Ub-positive protein aggregates and degraded by autophagy depending on an LC3-interacting region (LIR) and LC3 family modifiers. Although NBR1 and p62 interact and form oligomers, they can function independently, as shown by autophagosomal clearance of NBR1 in p62-deficient cells. NBR1 was localized to Ub-positive inclusions in patients with liver dysfunction, and depletion of NBR1 abolished the formation of Ub-positive p62 bodies upon puromycin treatment of cells. We propose that NBR1 and p62 act as receptors for selective autophagosomal degradation of ubiquitinated targets.
                Bookmark

                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                14 September 2015
                28 October 2015
                5 November 2015
                05 May 2016
                : 527
                : 7576
                : 105-109
                Affiliations
                [1 ]Epigenetics Program, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
                [2 ]Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA
                [3 ]Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA
                [4 ]Institute of Cancer Sciences, University of Glasgow, Cancer Research UK Beatson Labs, Glasgow G61 1BD, United Kingdom
                [6 ]Department of Biochemistry & Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
                [7 ]Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
                [8 ]Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
                [9 ]Molecular Cancer Research Group, Institute of Medical Biology, University of Tromsø – The Arctic University of Norway, 9037 Tromsø, Norway
                Author notes
                [10 ]Correspondence should be addressed to S.L.B. ( bergers@ 123456upenn.edu )
                [5]

                Current address: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom

                Article
                NIHMS721360
                10.1038/nature15548
                4824414
                26524528

                Reprints and permissions information is available at www.nature.com/reprints.

                Categories
                Article

                Uncategorized

                Comments

                Comment on this article