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EMBO Rep. 2018 Oct 2. pii: e46512. doi: 10.15252/embr.201846512. [Epub ahead of print]

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

Author information

1
Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Kreuzlingen, Switzerland michael.basler@uni-konstanz.de marcus.groettrup@uni-konstanz.de.
2
Division of Immunology, Department of Biology, University of Konstanz, Konstanz, Germany.
3
Principia Biopharma, South San Francisco, CA, USA.
4
Konstanz Research School Chemical Biology (KoRS-CB), University of Konstanz, Konstanz, Germany.
5
Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
6
Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
7
Kezar Life Sciences, South San Francisco, CA, USA.

Abstract

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.

KEYWORDS:

autoimmune disease; immunoproteasome; immunoproteasome inhibitor design; proteasome

PMID:
30279279
DOI:
10.15252/embr.201846512

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