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The intermediate proteasome is constitutively expressed in pancreatic beta cells and upregulated by stimulatory, non-toxic concentrations of interleukin 1 β

View ORCID ProfileMuhammad Saad Khilji, Danielle Verstappen, Tina Dahlby, Michala Cecilie Burstein Prause, Celina Pihl, View ORCID ProfileSophie Emilie Bresson, View ORCID ProfileTenna Holgersen Bryde, Kristian Klindt, Dusan Zivkovic, Marie-Pierre Bousquet-Dubouch, Björn Tyrberg, Nils Billestrup, View ORCID ProfileThomas Mandrup-Poulsen, View ORCID ProfileMichal Tomasz Marzec
doi: https://doi.org/10.1101/753061
Muhammad Saad Khilji
Laboratory of Immuno-endocrinology, Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
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  • ORCID record for Muhammad Saad Khilji
Danielle Verstappen
Laboratory of Immuno-endocrinology, Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, DenmarkRadboud Universiteit, Nijmegen, Netherlands
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Tina Dahlby
Laboratory of Immuno-endocrinology, Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
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Michala Cecilie Burstein Prause
Section for Beta-cell Biology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
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Celina Pihl
Laboratory of Immuno-endocrinology, Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
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Sophie Emilie Bresson
Laboratory of Immuno-endocrinology, Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
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Tenna Holgersen Bryde
Laboratory of Immuno-endocrinology, Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
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Kristian Klindt
Laboratory of Immuno-endocrinology, Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
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Dusan Zivkovic
Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique, Université de Toulouse, 31077 Toulouse, France
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Marie-Pierre Bousquet-Dubouch
Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique, Université de Toulouse, 31077 Toulouse, France
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Björn Tyrberg
Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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Nils Billestrup
Section for Beta-cell Biology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
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Thomas Mandrup-Poulsen
Laboratory of Immuno-endocrinology, Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
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Michal Tomasz Marzec
Laboratory of Immuno-endocrinology, Inflammation, Metabolism and Oxidation Section, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
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  • ORCID record for Michal Tomasz Marzec
  • For correspondence: Michal@sund.ku.dk
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Abstract

A central and still open question regarding the pathogenesis of autoimmune diseases, such as type 1 diabetes, concerns the processes that underlie the generation of MHC-presented autoantigenic epitopes that become targets of autoimmune attack. Proteasomal degradation is a key step in processing of proteins for MHC class I presentation. Different types of proteasomes can be expressed in cells dictating the repertoire of peptides presented by the MHC class I complex. Of particular interest for type 1 diabetes is the proteasomal configuration of pancreatic β cells, as this might facilitate autoantigen presentation by β cells and thereby their T-cell mediated destruction. Here we investigated whether so-called inducible subunits of the proteasome are constitutively expressed in β cells, regulated by inflammatory signals and participate in the formation of active intermediate or immuno-proteasomes.

We show that inducible proteasomal subunits are constitutively expressed in human and rodent islets and an insulin-secreting cell-line. Moreover, the β5i subunit is incorporated into active intermediate proteasomes that are bound to 19S or 11S regulatory particles. Finally, inducible subunit expression along with increase in total proteasome activities are further upregulated by non-toxic concentrations of IL-1β stimulating proinsulin biosynthesis. These findings suggest that the β cell proteasomal repertoire is more diverse than assumed previously and may be highly responsive to a local inflammatory islet environment.

  • Abbreviations

    i-proteasome
    Immunoproteasome
    int-proteasome
    Intermediate proteasome
    s-proteasome
    Standard proteasome
    β1
    beta subunit 1
    β2
    beta subunit 2
    β5
    beta subunit 5
    β1i
    inducible beta subunit 1
    β2i
    inducible beta subunit 2
    β5i
    inducible beta subunit 5
    PSMB8
    Proteasome subunit beta type-8 = β5i
    PSMB9
    Proteasome subunit beta type-9 = β1i
    PSMB10
    Proteasome subunit beta type-10 = β2i
    HBSS
    Hank’s balanced salt solution
    IL-1β
    Interleukin 1 β
    INF
    Interferon
    MHC
    Major histocompatibility complex
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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    Posted August 30, 2019.
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    The intermediate proteasome is constitutively expressed in pancreatic beta cells and upregulated by stimulatory, non-toxic concentrations of interleukin 1 β
    Muhammad Saad Khilji, Danielle Verstappen, Tina Dahlby, Michala Cecilie Burstein Prause, Celina Pihl, Sophie Emilie Bresson, Tenna Holgersen Bryde, Kristian Klindt, Dusan Zivkovic, Marie-Pierre Bousquet-Dubouch, Björn Tyrberg, Nils Billestrup, Thomas Mandrup-Poulsen, Michal Tomasz Marzec
    bioRxiv 753061; doi: https://doi.org/10.1101/753061
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    The intermediate proteasome is constitutively expressed in pancreatic beta cells and upregulated by stimulatory, non-toxic concentrations of interleukin 1 β
    Muhammad Saad Khilji, Danielle Verstappen, Tina Dahlby, Michala Cecilie Burstein Prause, Celina Pihl, Sophie Emilie Bresson, Tenna Holgersen Bryde, Kristian Klindt, Dusan Zivkovic, Marie-Pierre Bousquet-Dubouch, Björn Tyrberg, Nils Billestrup, Thomas Mandrup-Poulsen, Michal Tomasz Marzec
    bioRxiv 753061; doi: https://doi.org/10.1101/753061

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