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

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2018
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Lindstrom, Michelle M.
LaStant, Jacob J.
Bradshaw, J. Michael
Owens, Timothy D.
Maurits, Elmer
Tsu, Christopher
Overkleeft, Herman S.
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EMBO reports. 2018, 19(12), e46512. ISSN 1469-221X. eISSN 1469-3178. Available under: doi: 10.15252/embr.201846512
Zusammenfassung

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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570 Biowissenschaften, Biologie
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autoimmune disease, immunoproteasome, immunoproteasome inhibitor design, proteasome
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ISO 690BASLER, Michael, Michelle M. LINDSTROM, Jacob J. LASTANT, J. Michael BRADSHAW, Timothy D. OWENS, Christian SCHMIDT, Elmer MAURITS, Christopher TSU, Herman S. OVERKLEEFT, Marcus GRÖTTRUP, 2018. Co-inhibition of immunoproteasome subunits LMP2 and LMP7 is required to block autoimmunity. In: EMBO reports. 2018, 19(12), e46512. ISSN 1469-221X. eISSN 1469-3178. Available under: doi: 10.15252/embr.201846512
BibTex
@article{Basler2018-12-05Coinh-43584,
  year={2018},
  doi={10.15252/embr.201846512},
  title={Co-inhibition of immunoproteasome subunits LMP2 and LMP7 is required to block autoimmunity},
  number={12},
  volume={19},
  issn={1469-221X},
  journal={EMBO reports},
  author={Basler, Michael and Lindstrom, Michelle M. and LaStant, Jacob J. and Bradshaw, J. Michael and Owens, Timothy D. and Schmidt, Christian and Maurits, Elmer and Tsu, Christopher and Overkleeft, Herman S. and Gröttrup, Marcus},
  note={Article Number: e46512}
}
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