Proteasome subunit beta type-9 (LMP2) and Proteasome subunit beta type-10 (MECL1) (LMP2/MECL1)

The immunoproteasome is a specialized proteolytic complex induced by pro-inflammatory cytokines such as interferon-gamma and tumor necrosis factor-alpha. It differs from the constitutive proteasome by the incorporation of three distinct catalytic subunits: Proteasome subunit beta type-9 (LMP2) and Proteasome subunit beta type-10 (MECL1), along with LMP7 (UniProt P28065, P40306). These subunits, specifically LMP2 and MECL1, are responsible for altered cleavage patterns that generate peptides with high affinity for MHC class I molecules, thereby facilitating antigen presentation to CD8+ T cells (PubMed 29422541). Beyond antigen processing, these subunits regulate the activation of the NF-kappaB pathway and the production of various pro-inflammatory cytokines, making them attractive targets for treating autoimmune and inflammatory diseases (PubMed 33568475). Drugs like zetomipzomib (KZR-616) are designed to selectively inhibit these subunits to dampen overactive immune responses while avoiding the systemic toxicity seen with non-selective proteasome inhibitors like bortezomib (Kezar Life Sciences). Research indicates that targeting LMP2 and MECL1 can effectively treat conditions such as systemic lupus erythematosus and lupus nephritis by modulating T-cell and B-cell functions.

Other names

PSMB9PSMB10beta1ibeta2iRING12Low molecular mass polypeptide 2Multicatalytic endopeptidase complex-like 1Macropain chain 7Proteasome subunit beta type-9Proteasome subunit beta type-10

Selective inhibition of the catalytic threonine residues within the LMP2 and MECL1 subunits of the immunoproteasome to modulate antigen presentation and pro-inflammatory cytokine production.