Therapeutic Potential of Immunoproteasome Inhibition in Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy is an inherited fatal genetic disease characterized by mutations in dystrophin gene, causing membrane fragility leading to myofiber necrosis and inflammatory cell recruitment in dystrophic muscles. The resulting environment enriched in proinflammatory cytokines, like IFN-γ and TNF-α, determines the transformation of myofiber constitutive proteasome into the immunoproteasome, a multisubunit complex involved in the activation of cell-mediate immunity. This event has a fundamental role in producing peptides for antigen presentation by MHC class I, for the immune response and also for cytokine production and T-cell differentiation. Here, we characterized for the first time the presence of T-lymphocytes activated against revertant dystrophin epitopes, in the animal model of Duchenne muscular dystrophy, the mdx mice. Moreover, we specifically blocked i-proteasome subunit LMP7, which was up-regulated in dystrophic skeletal muscles, and we demonstrated the rescue of the dystrophin expression and the amelioration of the dystrophic phenotype. The i-proteasome blocking lowered myofiber MHC class I expression and self-antigen presentation to T cells, thus reducing the specific antidystrophin T cell response, the muscular cell infiltrate, and proinflammatory cytokine production, together with muscle force recovery. We suggest that i-proteasome inhibition should be considered as new promising therapeutic approach for Duchenne muscular dystrophy pathology.

The Immunoproteasome: An Emerging Target in Cancer and Autoimmune and Neurological Disorders.

The immunoproteasome (iCP) is an isoform of the 20S proteasome that is expressed when cells are stressed or receive an inflammatory signal. The primary role of the iCP is to hydrolyze proteins into peptides that are compatible with being loaded into a MHC-I complex. When the activity of the iCP is dysregulated or highly expressed, it can lead to unwanted cell death. Some cancer types express the iCP rather than the standard proteasome, and selective inhibitors have been developed to exploit this difference. Here, we describe diseases known to be influenced by iCP activity and the current status for targeting the iCP to elicit a therapeutic response. We also describe a variety of chemical tools that have been developed to monitor the activity of the iCP in cells. Finally, we present the future outlook for targeting the iCP in a variety of disease types and with mechanisms besides inhibition.

Immunoproteasome-specific inhibitors and their application.

Immunoproteasomes (IPs) containing the interferon-inducible subunits ß1i (LMP2), ß2i (MECL-1), and ß5i (LMP7) alter proteasomal cleavage preference, optimise the generation of peptide ligands of MHC class I molecules, alter cytokine profile, influence T-helper cell differentiation, and play a role in T-cell survival. Small molecule inhibitors are useful tools for probing the role of the immunoproteasome in immune functions. Here, we describe different methods to characterise immunoproteasome-selective inhibitors. Thereby, we provide the methodology to analyse the specificity and cell permeability of immunoproteasome inhibitors, as well as to functionally investigate immunoproteasome inhibitors in antigen presentation.