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Co-inhibition of immunoproteasome subunits LMP2 and LMP7 is required to block autoimmunity.

  • Basler M Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Kreuzlingen, Switzerland michael.basler@uni-konstanz.de marcus.groettrup@uni-konstanz.de.
  • Lindstrom MM Principia Biopharma, South San Francisco, CA, USA.
  • LaStant JJ Principia Biopharma, South San Francisco, CA, USA.
  • Bradshaw JM Principia Biopharma, South San Francisco, CA, USA.
  • Owens TD Principia Biopharma, South San Francisco, CA, USA.
  • Schmidt C Division of Immunology, Department of Biology, University of Konstanz, Konstanz, Germany.
  • Maurits E Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
  • Tsu C Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
  • Overkleeft HS Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
  • Kirk CJ Kezar Life Sciences, South San Francisco, CA, USA.
  • Langrish CL Principia Biopharma, South San Francisco, CA, USA.
  • Groettrup M Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Kreuzlingen, Switzerland michael.basler@uni-konstanz.de marcus.groettrup@uni-konstanz.de.
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  • 2018-10-04
Published in:
  • EMBO reports. - 2018
autoimmune disease
immunoproteasome
immunoproteasome inhibitor design
proteasome
Animals
Autoimmunity
Cell Differentiation
Cell Membrane Permeability
Colitis
Cytokines
Dextran Sulfate
Encephalomyelitis, Autoimmune, Experimental
Epitopes
Histocompatibility Antigens Class I
Mice, Inbred C57BL
Proteasome Endopeptidase Complex
Proteasome Inhibitors
Protein Subunits
Spleen
Th17 Cells
English Cells of hematopoietic origin express high levels of the immunoproteasome, a cytokine-inducible proteasome variant comprising the proteolytic subunits LMP2 (β1i), MECL-1 (β2i), and LMP7 (β5i). Targeting the immunoproteasome in pre-clinical models of autoimmune diseases with the epoxyketone inhibitor ONX 0914 has proven to be effective. ONX 0914 was previously described as a selective LMP7 inhibitor. Here, we show that PRN1126, developed as an exclusively LMP7-specific inhibitor, has limited effects on IL-6 secretion, experimental colitis, and experimental autoimmune encephalomyelitis (EAE). We demonstrate that prolonged exposure of cells with ONX 0914 leads to inhibition of both LMP7 and LMP2. Co-inhibition of LMP7 and LMP2 with PRN1126 and LMP2 inhibitors LU-001i or ML604440 impairs MHC class I cell surface expression, IL-6 secretion, and differentiation of naïve T helper cells to T helper 17 cells, and strongly ameliorates disease in experimental colitis and EAE. Hence, co-inhibition of LMP2 and LMP7 appears to be synergistic and advantageous for the treatment of autoimmune diseases.
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  • English
Open access status
green
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https://sonar.ch/global/documents/223795
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