41
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      CYLD negatively regulates transforming growth factor-β-signalling via deubiquitinating Akt

      research-article

      Read this article at

      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

          Lung injury, whether induced by infection or caustic chemicals, initiates a series of complex wound-healing responses. If uncontrolled, these responses may lead to fibrotic lung diseases and loss of function. Thus, resolution of lung injury must be tightly regulated. The key regulatory proteins required for tightly controlling the resolution of lung injury have yet to be identified. Here we show that loss of deubiquitinase CYLD led to the development of lung fibrosis in mice after infection with Streptococcus pneumoniae. CYLD inhibited transforming growth factor-β-signalling and prevented lung fibrosis by decreasing the stability of Smad3 in an E3 ligase carboxy terminus of Hsc70-interacting protein-dependent manner. Moreover, CYLD decreases Smad3 stability by deubiquitinating K63-polyubiquitinated Akt. Together, our results unveil a role for CYLD in tightly regulating the resolution of lung injury and preventing fibrosis by deubiquitinating Akt. These studies may help develop new therapeutic strategies for preventing lung fibrosis.

          Abstract

          Lung injury initiates a series of wound-healing responses, which if unregulated, can lead to fibrosis. Li et al. show that the deubquitinase CYLD has a key role in the prevention of fibrosis by inhibiting transforming growth factor β-signalling through the direct deubiquitination of the protein kinase Akt.

          Related collections

          Most cited references35

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

          Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B.

          Glycogen synthase kinase-3 (GSK3) is implicated in the regulation of several physiological processes, including the control of glycogen and protein synthesis by insulin, modulation of the transcription factors AP-1 and CREB, the specification of cell fate in Drosophila and dorsoventral patterning in Xenopus embryos. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k). Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The E3 ligase TRAF6 regulates Akt ubiquitination and activation.

            Akt signaling plays a central role in many biological functions, such as cell proliferation and apoptosis. Because Akt (also known as protein kinase B) resides primarily in the cytosol, it is not known how these signaling molecules are recruited to the plasma membrane and subsequently activated by growth factor stimuli. We found that the protein kinase Akt undergoes lysine-63 chain ubiquitination, which is important for Akt membrane localization and phosphorylation. TRAF6 was found to be a direct E3 ligase for Akt and was essential for Akt ubiquitination, membrane recruitment, and phosphorylation upon growth-factor stimulation. The human cancer-associated Akt mutant displayed an increase in Akt ubiquitination, in turn contributing to the enhancement of Akt membrane localization and phosphorylation. Thus, Akt ubiquitination is an important step for oncogenic Akt activation.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              New insights into TGF-beta-Smad signalling.

              Transforming growth factor beta (TGF-beta) initiates its diverse cellular responses by binding to and activating specific cell surface receptors that have intrinsic serine/threonine kinase activity. These activated TGF-beta receptors stimulate the phosphorylation of receptor-regulated Smad proteins, which in turn form complexes with Smad4 that accumulate in the nucleus and regulate the transcription of target genes. TGF-beta responses can be cell-type specific and are dependent on both the concentration of TGF-beta signalling components and the activity of other signal transduction pathways, which can either synergize with or antagonize the TGF-beta pathway. Recent research has provided insights into the specificity determinants of TGF-beta-Smad signalling, including combinatorial ligand-receptor associations, selective interactions between the Smads and other pathway components that are mediated through defined binding motifs, and the differential regulation of duration and intensity of signalling.
                Bookmark

                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Pub. Group
                2041-1723
                10 April 2012
                : 3
                : 771
                Affiliations
                [1 ]simpleCenter for Inflammation, Immunity & Infection and Department of Biology, Georgia State University , Atlanta, 30303, USA.
                [2 ]simpleDepartment of Microbiology & Immunology, University of Rochester Medical Center , New York 14642, USA.
                [3 ]simpleDepartment of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University , 862-0973, Japan.
                [4 ]simpleDepartment of Pharmacology, College of Medicine, Yeungnam University , Daegu 705-717, Korea.
                [5 ]simpleDepartment of Infectious Disease, Huashan Hospital, Fudan University , Shanghai 200040, China.
                [6 ]simpleDepartment of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University , Gwangju 500-757, Korea.
                [7 ]simpleInternal Medicine , Gwangju 500-757, Korea.
                [8 ]simplePathology, Chonnam National University & Hospital , Gwangju 500-757, Korea.
                [9 ]simpleDepartment of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine and State Key Lab of Respiratory Diseases , Hangzhou 310009, China.
                [10 ]simpleCardiovascular Research Institute, University of Rochester Medical Center , New York 14642, USA.
                [11 ]simpleDepartment of Pathology & Laboratory Medicine, University of Rochester Medical Center , New York 14642, USA.
                [12 ]simpleDepartment of Chemistry & Center for Diagnostics and Therapeutics, Georgia State University , Atlanta, 30303, USA.
                [13 ]simpleDepartment of Biochemistry, College of Medicine, University of Illinois at Urbana-Champaign , 61801, USA.
                [14 ]simpleLife Sciences Institute, Zhejiang University , Hangzhou 310058, China.
                [15 ]simpleDepartment of Molecular and Cellular Biology, Baylor College of Medicine , Houston, Texas 77030, USA.
                [16 ]These authors contributed equally to this work.
                Author notes
                Article
                ncomms1776
                10.1038/ncomms1776
                3337989
                22491319
                5035af3f-0515-4ba8-9787-c86e18186036
                Copyright © 2012, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                : 16 September 2011
                : 07 March 2012
                Categories
                Article

                Uncategorized
                Uncategorized

                Comments

                Comment on this article