The Immunoproteasome in Health and Disease

Dear Colleagues,

The immunoproteasome is a cytokine-inducible variant of the standard proteasome in which the catalytically active subunits β1, β2, and β5 are replaced by the subunits β1i (LMP2), β2i (MECL-1), and β5i (LMP7). This subunit replacement changes the cleavage preferences of the proteasome and largely affects the generation of peptide ligands of MHC class I molecules. After 20 years of intensive study of the role of the immunoproteasome in antigen processing, 10 years ago, it was discovered that the immunoproteasome fulfills additional functions that are unrelated to antigen processing. With the help of immunoproteasome-selective inhibitors and gene-targeted mice, it could be shown that immunoproteasomes promote the differentiation of pro-inflammatory T helper cell subsets (Th1, Th17) and the production of pro-inflammatory cytokines (e.g., interferons, TNF, IL-6, IL-17, IL-23). These are involved in the development and persistence of autoimmune diseases, which may explain why immunoproteasome inhibition suppresses numerous autoimmune diseases as well as the chronic rejection of allotransplants in pre-clinical models. Excitingly, immunoproteasome inhibitors are presently tested as therapeutics against autoimmune diseases and cancer in humans. The almost exclusive expression of immunoproteasomes in virtually all types of immune cells poses questions about a potential special function of immunoproteasomes in leukocytes, which is currently being investigated. The renewed interest in immunoproteasome function is the impetus for compiling this Special Issue, which is exclusively dedicated to immunoproteasome research. Topics that will be covered in this issue include:

• Structure—function relationship of the immunoproteasome;
• Selective association of the immunoproteasome with proteasome regulators;
• Functional differences between standard, intermediate, and immunoproteasomes;
• The immunoproteasome in antigen processing and presentation;
• The role of the immunoproteasome in proteostasis;
• The evolution of the immunoproteasome;
• The regulation of immunoproteasome expression;
• The impact of the immunoproteasome on T cell activation and differentiation;
• The function of the immunoproteasome in inflammation;
• The therapeutic potential of immunoproteasome inhibitors in autoimmunity, inflammatory diseases, and cancer;
• Interference with transplant rejection by immunoproteasome inhibitors;
• The development of immunoproteasome selective inhibitors;
• The clinical achievements obtained with immunoproteasome inhibitors.

Prof. Dr. Marcus Groettrup
Dr. Michael Basler
Guest Editors

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