Cysteine cathepsins activate ELR chemokines and inactivate non-ELR chemokines [Molecular Bases of Disease]

April 1st, 2015 by Repnik, U., Starr, A. E., Overall, C. M., Turk, B.

Cysteine cathepsins are primarily lysosomal proteases involved in general protein turnover, but also have specific proteolytic functions in antigen presentation and bone remodeling. Cathepsins are most stable at acidic pH, although growing evidence indicates that they have physiologically relevant activity also at neutral pH. Post-translational proteolytic processing of mature chemokines is a key, yet underappreciated level of chemokine regulation. Although the role of selected serine proteases and matrix metalloproteases in chemokine processing is long known, little is reported about the role of cysteine cathepsins. Here we evaluated cleavage of CXC ELR (CXCL1, 2, 3, 5, 8) and non-ELR (CXCL9, 10, 11, 12) chemokines by cysteine cathepsins B, K, L and S at neutral pH by high resolution Tris-Tricine SDS-PAGE and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Whereas cathepsin B cleaved chemokines especially in the C-terminal region, cathepsins K, L and S cleaved chemokines at the N-terminus with glycosaminoglycans modulating cathepsin processing of chemokines. The functional consequences of the cleavages were determined by Ca2+ mobilization and chemotaxis assays. We show that cysteine cathepsins inactivate and in some cases degrade non-ELR CXC chemokines CXCL9, 10, 11 and 12. In contrast, cathepsins specifically process ELR CXC chemokines CXCL1, 2, 3, 5, and 8 N-terminal to the ELR motif thereby generating agonist forms. This study suggests that cysteine cathepsins regulate chemokine activity and thereby leukocyte recruitment during protective or pathological inflammation.