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      A Novel Role for ATM in Regulating Proteasome-Mediated Protein Degradation through Suppression of the ISG15 Conjugation Pathway

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          Abstract

          Ataxia Telangiectasia (A-T) is an inherited immunodeficiency disorder wherein mutation of the ATM kinase is responsible for the A-T pathogenesis. Although the precise role of ATM in A-T pathogenesis is still unclear, its function in responding to DNA damage has been well established. Here we demonstrate that in addition to its role in DNA repair, ATM also regulates proteasome-mediated protein turnover through suppression of the ISG15 pathway. This conclusion is based on three major pieces of evidence: First, we demonstrate that proteasome-mediated protein degradation is impaired in A-T cells. Second, we show that the reduced protein turnover is causally linked to the elevated expression of the ubiquitin-like protein ISG15 in A-T cells. Third, we show that expression of the ISG15 is elevated in A-T cells derived from various A-T patients, as well as in brain tissues derived from the ATM knockout mice and A-T patients, suggesting that ATM negatively regulates the ISG15 pathway. Our current findings suggest for the first time that proteasome-mediated protein degradation is impaired in A-T cells due to elevated expression of the ISG15 conjugation pathway, which could contribute to progressive neurodegeneration in A-T patients.

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          Most cited references 61

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          Interferon-inducible antiviral effectors.

          Since the discovery of interferons (IFNs), considerable progress has been made in describing the nature of the cytokines themselves, the signalling components that direct the cell response and their antiviral activities. Gene targeting studies have distinguished four main effector pathways of the IFN-mediated antiviral response: the Mx GTPase pathway, the 2',5'-oligoadenylate-synthetase-directed ribonuclease L pathway, the protein kinase R pathway and the ISG15 ubiquitin-like pathway. As discussed in this Review, these effector pathways individually block viral transcription, degrade viral RNA, inhibit translation and modify protein function to control all steps of viral replication. Ongoing research continues to expose additional activities for these effector proteins and has revealed unanticipated functions of the antiviral response.
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            Atypical ubiquitin chains: new molecular signals. 'Protein Modifications: Beyond the Usual Suspects' review series.

             F Ikeda,  Ivan Dikic (2008)
            Ubiquitin (Ub) is a small protein modifier that regulates many biological processes, including gene transcription, cell-cycle progression, DNA repair, apoptosis, virus budding and receptor endocytosis. Ub can be conjugated to target proteins either as a monomer or as Ub chains that vary in length and linkage type. The various types of Ub modification are linked to distinct physiological functions in cells. MonoUb, for example, regulates DNA repair and receptor endocytosis, whereas lysine 48-linked Ub chains label proteins for proteasomal degradation. More recently, the importance of chains conjugated through the other six lysines in Ub, known as atypical Ub chains, has been revealed. Atypical chains can be homotypic, sequentially using the same lysine residue in Ub for conjugation; mixed-linkage, utilizing several distinct lysines to connect consecutive Ub moieties; or heterologous, connecting Ub with other Ub-like modifiers. Here, we describe recent progress in the understanding of atypical Ub chain assembly and their recognition by Ub-binding domains, and we discuss further their functional roles in vivo.
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              Principles of ubiquitin and SUMO modifications in DNA repair.

              With the discovery in the late 1980s that the DNA-repair gene RAD6 encodes a ubiquitin-conjugating enzyme, it became clear that protein modification by ubiquitin conjugation has a much broader significance than had previously been assumed. Now, two decades later, ubiquitin and its cousin SUMO are implicated in a range of human diseases, including breast cancer and Fanconi anaemia, giving fresh momentum to studies focused on the relationships between ubiquitin, SUMO and DNA-repair pathways.
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                Author and article information

                Affiliations
                [1 ]Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
                [2 ]Department of Biochemistry and Molecular Biology, Louisiana State University of Health Sciences Center-School of Medicine, New Orleans, Louisiana, United States of America
                [3 ]Department of Pharmacology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey, United States of America
                [4 ]Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America
                Karolinska Institutet, Sweden
                Author notes

                Conceived and designed the experiments: SDD. Performed the experiments: SDD LMW SS RER. Analyzed the data: SDD LMW SS ALH LFL. Contributed reagents/materials/analysis tools: PM ALH. Wrote the paper: SDD. Edited the final version of the manuscript: LFL ALH.

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                26 January 2011
                : 6
                : 1
                3027683
                21298066
                PONE-D-10-04137
                10.1371/journal.pone.0016422
                (Editor)
                This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
                Counts
                Pages: 12
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Cell Physiology
                Biochemistry
                Proteins
                Conjugated Proteins
                Molecular Cell Biology
                Neuroscience
                Neurobiology of Disease and Regeneration
                Medicine
                Neurology
                Movement Disorders
                Ataxia-Telangiectasia

                Uncategorized

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