Cathepsin G: roles in antigen presentation and beyond

Abstract

Contributions from multiple cathepsins within endosomal antigen processing compartments are necessary to process antigenic proteins into antigenic peptides. Cysteine and aspartyl cathepsins have been known to digest antigenic proteins. A role for the serine protease, cathepsin G (CatG), in this process has been described only recently, although CatG has long been known to be a granule-associated proteolytic enzyme of neutrophils. In line with a role for this enzyme in antigen presentation, CatG is found in endocytic compartments of a variety of antigen presenting cells. CatG is found in primary human monocytes, B cells, myeloid dendritic cells 1 (mDC1), mDC2, plasmacytoid DC (pDC), and murine microglia, but is not expressed in B cell lines or monocyte-derived DC. Purified CatG can be internalized into endocytic compartments in CatG non-expressing cells, widening the range of cells where this enzyme may play a role in antigen processing. Functional assays have implicated CatG as a critical enzyme in processing of several antigens and autoantigens. In this review, historical and recent data on CatG expression, distribution, function and involvement in disease will be summarized and discussed, with a focus on its role in antigen presentation and immune-related events.

Figure 1. Substrate specificity of CatG

Clevage site of the protease is determined between P1 and P1′position. X=represent all 20 amino acids.

Figure 2. A model of antigen processing in primary CD22⁺ B cells

Activated granulocytes secret CatG into the plasma. CatG non-expressing, circulating B cells bind CatG via a thrombin-like receptor and internalize CatG into endocytic compartments. In these compartments, CatG functions as an additional protease and may improve the generation of antigenic ligands that replace CLIP on MHC class II molecules, a process facilitated by DM. The resulting MHC class II-antigenic peptide complex traffics to the cell surface for inspection by CD4⁺ T cells. Cat, cathepsin; CLIP, class II-associated Ii peptides; DM, HLA-DM; DO, HLA-DO; HLA, human leukocyte antigen; li, MHC class II invariant chain; MBP, myelin basic protein; MHC, major histocompatibility complex.