Basler M Lindstrom MM LaStant JJ Bradshaw JM Owens TD Schmidt C Maurits E Tsu C Overkleeft HS Kirk CJ Langrish CL Groettrup M 2018 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. application/pdf https://sonar.ch/global/documents/223795 eng info:eu-repo/semantics/altIdentifier/doi/10.15252/embr.201846512 info:eu-repo/semantics/altIdentifier/pmid/30279279 info:eu-repo/semantics/openAccess 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 Co-inhibition of immunoproteasome subunits LMP2 and LMP7 is required to block autoimmunity. http://purl.org/coar/resource_type/c_6501