Research Summary
Functional responsibilities of cathepsin G (CatG) in immunity, including bivalent regulation of major histocompatibility complex class I (MHC) molecules, which underscore a novel role of CatG within the immune system.
Special Interests: Immune evasion of tumor cells and pathogens, modulating of the proteolytic activity of CatG, functional properties of CatG in T cells, immunosenescence
Timo Burster, Associate Professor Email: timo.burster@nu.edu.kz
Fig. 1: Three-dimensional structure of human cathepsin G (CatG).
The catalytic triad is shown: H57, D102, and S195 and the N-linked glycosylation site is found at N65. The polymorphism within the coding region is labeled as N119S. PDB: 1CGH P. Based on Hof, I et al., EMBO J, 15 (1996) 5481-5491.
Fig. 2: A model of how exogenous CatG modulates cell surface expression of MHC I.
CatG proteolytically cleaves the N-terminal end of the extracellular domain of protease-activated receptor 1 (PAR1). As a result, the tethered activation ligand flips to the extracellular loop 2 and recruits intracellular G protein, which is capable of downstream signal transduction.
However, cleavage of the extracellular part of PAR1 by CatG can also lead to receptor inactivation, so-called dis-arming; thereby the tethered ligand as well as three extracellular loops of PAR1 are digested and blocks G protein-mediated signaling. This can be further enhanced by the interaction of lactoferrin (LF) with CatG. LF increases the proteolytic activity of CatG and augments a CatG-mediated upregulation of MHC I molecules on the cell surface. The MHC I recycling pathway, for instance, is important for loading a new set of antigenic peptides (viral derived or tumor-associated) to MHC I molecules in order to be displayed on the cell surface for CD8+ T cell inspection. Distinct viruses or tumor cells prevent the synthesis of nascent MHC I molecules or interfere with the MHC I recycling pathway. The advantage of CatG-mediated upregulation of cell surface MHC I molecules is the efficacy to reuse MHC I within the MHC I recycling pathway, where MHC I molecules are pushed out to the cell surface instead of being degraded in the lysosome, as an additional model regarding how CatG circumvents immune evasion of viruses or tumor cells.
