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      Proteolysis of mature HIV-1 p6 Gag protein by the insulin-degrading enzyme (IDE) regulates virus replication in an Env-dependent manner

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          Abstract

          There is a significantly higher risk for type II diabetes in HIV-1 carriers, albeit the molecular mechanism for this HIV-related pathology remains enigmatic. The 52 amino acid HIV-1 p6 Gag protein is synthesized as the C-terminal part of the Gag polyprotein Pr55. In this context, p6 promotes virus release by its two late (L-) domains, and facilitates the incorporation of the viral accessory protein Vpr. However, the function of p6 in its mature form, after proteolytic release from Gag, has not been investigated yet. We found that the mature p6 represents the first known viral substrate of the ubiquitously expressed cytosolic metalloendopeptidase insulin-degrading enzyme (IDE). IDE is sufficient and required for degradation of p6, and p6 is approximately 100-fold more efficiently degraded by IDE than its eponymous substrate insulin. This observation appears to be specific for HIV-1, as p6 proteins from HIV-2 and simian immunodeficiency virus, as well as the 51 amino acid p9 from equine infectious anaemia virus were insensitive to IDE degradation. The amount of virus-associated p6, as well as the efficiency of release and maturation of progeny viruses does not depend on the presence of IDE in the host cells, as it was shown by CRISPR/Cas9 edited IDE KO cells. However, HIV-1 mutants harboring IDE-insensitive p6 variants exhibit reduced virus replication capacity, a phenomenon that seems to depend on the presence of an X4-tropic Env. Furthermore, competing for IDE by exogenous insulin or inhibiting IDE by the highly specific inhibitor 6bK, also reduced virus replication. This effect could be specifically attributed to IDE since replication of HIV-1 variants coding for an IDE-insensitive p6 were inert towards IDE-inhibition. Our cumulative data support a model in which removal of p6 during viral entry is important for virus replication, at least in the case of X4 tropic HIV-1.

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          JCat: a novel tool to adapt codon usage of a target gene to its potential expression host

          Andreas Gerber Grote, Karsten Hiller, Maurice Scheer … (2005)
          A novel method for the adaptation of target gene codon usage to most sequenced prokaryotes and selected eukaryotic gene expression hosts was developed to improve heterologous protein production. In contrast to existing tools, JCat (Java Codon Adaptation Tool) does not require the manual definition of highly expressed genes and is, therefore, a very rapid and easy method. Further options of JCat for codon adaptation include the avoidance of unwanted cleavage sites for restriction enzymes and Rho-independent transcription terminators. The output of JCat is both graphically and as Codon Adaptation Index (CAI) values given for the pasted sequence and the newly adapted sequence. Additionally, a list of genes in FASTA-format can be uploaded to calculate CAI values. In one example, all genes of the genome of Caenorhabditis elegans were adapted to Escherichia coli codon usage and further optimized to avoid commonly used restriction sites. In a second example, the Pseudomonas aeruginosa exbD gene codon usage was adapted to E.coli codon usage with parallel avoidance of the same restriction sites. For both, the degree of introduced changes was documented and evaluated. JCat is integrated into the PRODORIC database that hosts all required information on the various organisms to fulfill the requested calculations. JCat is freely accessible at .
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            Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo.

            Wesley Farris, Stefan Mansourian, Yang Chang … (2003)
            Two substrates of insulin-degrading enzyme (IDE), amyloid beta-protein (Abeta) and insulin, are critically important in the pathogenesis of Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2), respectively. We previously identified IDE as a principal regulator of Abeta levels in neuronal and microglial cells. A small chromosomal region containing a mutant IDE allele has been associated with hyperinsulinemia and glucose intolerance in a rat model of DM2. Human genetic studies have implicated the IDE region of chromosome 10 in both AD and DM2. To establish whether IDE hypofunction decreases Abeta and insulin degradation in vivo and chronically increases their levels, we characterized mice with homozygous deletions of the IDE gene (IDE --). IDE deficiency resulted in a >50% decrease in Abeta degradation in both brain membrane fractions and primary neuronal cultures and a similar deficit in insulin degradation in liver. The IDE -- mice showed increased cerebral accumulation of endogenous Abeta, a hallmark of AD, and had hyperinsulinemia and glucose intolerance, hallmarks of DM2. Moreover, the mice had elevated levels of the intracellular signaling domain of the beta-amyloid precursor protein, which was recently found to be degraded by IDE in vitro. Together with emerging genetic evidence, our in vivo findings suggest that IDE hypofunction may underlie or contribute to some forms of AD and DM2 and provide a mechanism for the recently recognized association among hyperinsulinemia, diabetes, and AD.
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              HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time.

              Victor Markowitz, Alan Perelson, Anthony Ho … (1996)
              A new mathematical model was used to analyze a detailed set of human immunodeficiency virus-type 1 (HIV-1) viral load data collected from five infected individuals after the administration of a potent inhibitor of HIV-1 protease. Productively infected cells were estimated to have, on average, a life-span of 2.2 days (half-life t 1/2 = 1.6 days), and plasma virions were estimated to have a mean life-span of 0.3 days (t 1/2 = 0.24 days). The estimated average total HIV-1 production was 10.3 x 10(9) virions per day, which is substantially greater than previous minimum estimates. The results also suggest that the minimum duration of the HIV-1 life cycle in vivo is 1.2 days on average, and that the average HIV-1 generation time--defined as the time from release of a virion until it infects another cell and causes the release of a new generation of viral particles--is 2.6 days. These findings on viral dynamics provide not only a kinetic picture of HIV-1 pathogenesis, but also theoretical principles to guide the development of treatment strategies.
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                Author and article information

                Contributors
                Fabrizio Mammano: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 7 April 2017
                Publication date Collection: 2017
                Volume: 12
                Issue: 4
                Electronic Location Identifier: e0174254
                Affiliations
                [1 ]Institute of Virology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
                [2 ]Translational Metabolism Unit, Diabetes Research Center, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, Texas, United States of America
                [3 ]Institute of Biochemistry, Charité Universitätsmedizin-Berlin, Berlin, Germany
                [4 ]Department of Chemistry and Centre for Pharmacy, University of Bergen, Bergen, Norway
                "INSERM", FRANCE
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: US AS FH.

                • Funding acquisition: US.

                • Investigation: FH AS CS MF SS J. Kölle RS PR KF TR J. Karius-Fischer PH TF.

                • Project administration: US.

                • Resources: PH.

                • Supervision: US.

                • Visualization: US FH AS CS MF SS J. Kölle RS TR TF.

                • Writing – original draft: US FH CS MF AS SS.

                • Writing – review & editing: AB US.

                Author information
                http://orcid.org/0000-0003-2462-2675
                http://orcid.org/0000-0003-4792-4991
                Article
                Publisher ID: PONE-D-16-42935
                DOI: 10.1371/journal.pone.0174254
                PMC ID: 5384750
                PubMed ID: 28388673
                SO-VID: f429f1ab-3b9a-4d02-9b0a-64e914e4be08
                Copyright © © 2017 Hahn et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 3 November 2016
                Date accepted : 6 March 2017
                Page count
                Figures: 11, Tables: 0, Pages: 29
                Funding
                Funded by: Deutsche Forschungsgemeinschaft (DE)
                Award ID: SFB643-A1
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: RO1 DK81553
                Award Recipient :
                Funded by: Interdisziplinäre Zentrum für Klinische Forschung (IZKF)
                Award ID: IZKF grant A70
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: graduate program GRK1071
                Award Recipient :
                US received funding from "Deutsche Forschungsgemeinschaft", grant number SFB643-A1, URL: http://gepris.dfg.de/gepris/projekt/5486111. US received funding from "Deutsche Forschungsgemeinschaft", graduate program GRK 1071, URL: http://gepris.dfg.de/gepris/projekt/440477. US received funding from "Interdisziplinaere Zentrum fuer Klinische Forschung (IZKF)", IZKF grant A70, URL: http://www.izkf.uk-erlangen.de/. US received funding from the NIH, grant RO1 DK81553, URL: https://grants.nih.gov/grants/funding/r01.htm. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Microbiology
                Subject: Medical Microbiology
                Subject: Microbial Pathogens
                Subject: Viral Pathogens
                Subject: Immunodeficiency Viruses
                Subject: HIV
                Subject: HIV-1
                Subject: Medicine and Health Sciences
                Subject: Pathology and Laboratory Medicine
                Subject: Pathogens
                Subject: Microbial Pathogens
                Subject: Viral Pathogens
                Subject: Immunodeficiency Viruses
                Subject: HIV
                Subject: HIV-1
                Subject: Biology and Life Sciences
                Subject: Organisms
                Subject: Viruses
                Subject: Viral Pathogens
                Subject: Immunodeficiency Viruses
                Subject: HIV
                Subject: HIV-1
                Subject: Biology and Life Sciences
                Subject: Organisms
                Subject: Viruses
                Subject: Immunodeficiency Viruses
                Subject: HIV
                Subject: HIV-1
                Subject: Biology and life sciences
                Subject: Organisms
                Subject: Viruses
                Subject: RNA viruses
                Subject: Retroviruses
                Subject: Lentivirus
                Subject: HIV
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                Subject: Biology and Life Sciences
                Subject: Microbiology
                Subject: Medical Microbiology
                Subject: Microbial Pathogens
                Subject: Viral Pathogens
                Subject: Retroviruses
                Subject: Lentivirus
                Subject: HIV
                Subject: HIV-1
                Subject: Medicine and Health Sciences
                Subject: Pathology and Laboratory Medicine
                Subject: Pathogens
                Subject: Microbial Pathogens
                Subject: Viral Pathogens
                Subject: Retroviruses
                Subject: Lentivirus
                Subject: HIV
                Subject: HIV-1
                Subject: Biology and Life Sciences
                Subject: Organisms
                Subject: Viruses
                Subject: Viral Pathogens
                Subject: Retroviruses
                Subject: Lentivirus
                Subject: HIV
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                Subject: Medicine and Health Sciences
                Subject: Endocrinology
                Subject: Diabetic Endocrinology
                Subject: Insulin
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Hormones
                Subject: Insulin
                Subject: Biology and Life Sciences
                Subject: Microbiology
                Subject: Virology
                Subject: Viral Replication
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                Subject: Microbiology
                Subject: Medical Microbiology
                Subject: Microbial Pathogens
                Subject: Viral Pathogens
                Subject: Immunodeficiency Viruses
                Subject: HIV
                Subject: HIV-2
                Subject: Medicine and Health Sciences
                Subject: Pathology and Laboratory Medicine
                Subject: Pathogens
                Subject: Microbial Pathogens
                Subject: Viral Pathogens
                Subject: Immunodeficiency Viruses
                Subject: HIV
                Subject: HIV-2
                Subject: Biology and Life Sciences
                Subject: Organisms
                Subject: Viruses
                Subject: Viral Pathogens
                Subject: Immunodeficiency Viruses
                Subject: HIV
                Subject: HIV-2
                Subject: Biology and Life Sciences
                Subject: Organisms
                Subject: Viruses
                Subject: Immunodeficiency Viruses
                Subject: HIV
                Subject: HIV-2
                Subject: Biology and life sciences
                Subject: Organisms
                Subject: Viruses
                Subject: RNA viruses
                Subject: Retroviruses
                Subject: Lentivirus
                Subject: HIV
                Subject: HIV-2
                Subject: Biology and Life Sciences
                Subject: Microbiology
                Subject: Medical Microbiology
                Subject: Microbial Pathogens
                Subject: Viral Pathogens
                Subject: Retroviruses
                Subject: Lentivirus
                Subject: HIV
                Subject: HIV-2
                Subject: Medicine and Health Sciences
                Subject: Pathology and Laboratory Medicine
                Subject: Pathogens
                Subject: Microbial Pathogens
                Subject: Viral Pathogens
                Subject: Retroviruses
                Subject: Lentivirus
                Subject: HIV
                Subject: HIV-2
                Subject: Biology and Life Sciences
                Subject: Organisms
                Subject: Viruses
                Subject: Viral Pathogens
                Subject: Retroviruses
                Subject: Lentivirus
                Subject: HIV
                Subject: HIV-2
                Subject: Biology and Life Sciences
                Subject: Microbiology
                Subject: Medical Microbiology
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                Subject: Immunodeficiency Viruses
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                Subject: Medicine and Health Sciences
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                Subject: Immunodeficiency Viruses
                Subject: SIV
                Subject: Biology and Life Sciences
                Subject: Organisms
                Subject: Viruses
                Subject: Viral Pathogens
                Subject: Immunodeficiency Viruses
                Subject: SIV
                Subject: Biology and Life Sciences
                Subject: Organisms
                Subject: Viruses
                Subject: Immunodeficiency Viruses
                Subject: SIV
                Subject: Biology and life sciences
                Subject: Organisms
                Subject: Viruses
                Subject: RNA viruses
                Subject: Retroviruses
                Subject: Lentivirus
                Subject: SIV
                Subject: Biology and Life Sciences
                Subject: Microbiology
                Subject: Medical Microbiology
                Subject: Microbial Pathogens
                Subject: Viral Pathogens
                Subject: Retroviruses
                Subject: Lentivirus
                Subject: SIV
                Subject: Medicine and Health Sciences
                Subject: Pathology and Laboratory Medicine
                Subject: Pathogens
                Subject: Microbial Pathogens
                Subject: Viral Pathogens
                Subject: Retroviruses
                Subject: Lentivirus
                Subject: SIV
                Subject: Biology and Life Sciences
                Subject: Organisms
                Subject: Viruses
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                Subject: Retroviruses
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                Subject: Research and Analysis Methods
                Subject: Database and Informatics Methods
                Subject: Bioinformatics
                Subject: Sequence Analysis
                Subject: Sequence Motif Analysis
                Subject: Biology and life sciences
                Subject: Molecular biology
                Subject: Molecular biology techniques
                Subject: DNA construction
                Subject: Plasmid Construction
                Subject: Research and analysis methods
                Subject: Molecular biology techniques
                Subject: DNA construction
                Subject: Plasmid Construction
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