Proteinase 3 (PR3) (PR3)

Proteinase 3 (PR3), also known as myeloblastin, is a 29 kDa serine protease primarily synthesized in neutrophil granulocytes and stored within their azurophilic granules. It serves as a vital component of the innate immune system by facilitating the intracellular degradation of phagocytosed pathogens and the extracellular processing of pro-inflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α. PR3 is uniquely distinguished from other neutrophil serine proteases by its prominent cell-surface expression, which acts as the major autoantigen in Granulomatosis with polyangiitis (GPA) and induces the production of pathogenic cytoplasmic anti-neutrophil cytoplasmic antibodies (c-ANCAs). In chronic inflammatory states, such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis, an imbalance between PR3 and its endogenous inhibitors leads to the degradation of extracellular matrix components like elastin and collagen, resulting in severe tissue damage and lung remodeling. Therapeutic interventions targeting PR3 include direct inhibitors like Tiprelestat and indirect agents like Brensocatib, which block the upstream enzyme dipeptidyl peptidase 1 (DPP1) to prevent the maturation and activation of PR3.

Other names

MyeloblastinNeutrophil proteinase 3Wegener autoantigenPRTN3NP-4AGP7P29c-ANCA antigenACPAMBT

The therapeutic targeting of proteinase 3 involves two primary strategies: (1) direct inhibition of the enzyme's catalytic activity by small molecules or recombinant proteins like elafin (Tiprelestat) and alpha-1 antitrypsin; and (2) indirect inhibition through dipeptidyl peptidase 1 (DPP1/cathepsin C) antagonists, such as brensocatib, which prevent the proteolytic activation of the proteinase 3 pro-enzyme during neutrophil maturation in the bone marrow.