Journal
EMBO REPORTS
Volume 19, Issue 12, Pages -Publisher
WILEY
DOI: 10.15252/embr.201846512
Keywords
autoimmune disease; immunoproteasome; immunoproteasome inhibitor design; proteasome
Categories
Funding
- German Research Foundation [BA 4199/2-1, GR 1517/2.4, GR 1517/10-2, SFB969]
- SwissLife Jubilaumsstiftung
- Swiss Cancer Research grant [KFS-3687-08-2015]
- Netherlands Organization of Scientific Research
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Cells of hematopoietic origin express high levels of the immunoproteasome, a cytokine-inducible proteasome variant comprising the proteolytic subunits LMP2 (beta 1i), MECL-1 (beta 2i), and LMP7 (beta 5i). 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 naive 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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