Immunoproteasome complex (IP)

The immunoproteasome complex is a specialized isoform of the 26S proteasome, primarily expressed in hematopoietic cells or induced in non-hematopoietic cells, such as mesenchymal stromal cells (MSCs), by inflammatory cytokines like interferon-gamma (IFN-gamma) (PMID: 23414511). It is distinguished from the constitutive proteasome by the replacement of its catalytic subunits with three inducible subunits: beta-1i (LMP2), beta-2i (MECL-1), and beta-5i (LMP7) (UniProt: P28062, P28065, P40306). In MSCs, the immunoproteasome plays a critical role in maintaining protein homeostasis and regulating their immunomodulatory capacity under inflammatory stress (PMID: 23606534). By altering the repertoire of peptides generated for MHC class I presentation and modulating the NF-kappaB signaling pathway, the immunoproteasome influences the secretion of pro-inflammatory cytokines and the overall immune-suppressive profile of MSCs (PMID: 21149606, PMID: 30245454). Therapeutically, selective inhibition of the immunoproteasome using agents like zetomipzomib (KZR-616) is being investigated for the treatment of autoimmune and inflammatory diseases, as it can dampen pathological immune responses with potentially fewer side effects than pan-proteasome inhibitors (Kezar Life Sciences). Understanding the function of this complex within MSCs is vital for enhancing the efficacy of cell-based therapies and managing conditions like graft-versus-host disease (PMID: 26162131).

Other names

20S immunoproteasomeInducible proteasomeLMP2/LMP7/MECL-1 complexi-proteasomeInducible 20S catalytic particle

Selective or non-selective inhibition of the catalytic subunits (beta-1i/LMP2, beta-2i/MECL-1, and beta-5i/LMP7) of the 20S core particle, which prevents the degradation of specific protein substrates, modulates the NF-kappaB signaling pathway, and reduces the production of pro-inflammatory cytokines.