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Function of Liver Activation-Regulated Chemokine/CC Chemokine Ligand 20 Is Differently Affected by Cathepsin B and Cathepsin D Processing¹

Lara Hasan^*, Luca Mazzucchelli^*,, Mark Liebi, Maddalena Lis^*, Robert E. Hunger, Angus Tester^,¶, Christopher M. Overall^,¶ and Marlene Wolf^2,

^* Institute of Pathology, Theodor-Kocher Institute, and Department of Dermatology, University of Bern, Bern, Switzerland; Istituto di Patologia, Locarno, Switzerland; and ^¶ Department of Biochemistry and Molecular Biology, Centre for Blood Research and the Canadian Institutes for Health Research Group in Matrix Dynamics, University of British Columbia, Vancouver, British Columbia, Canada

Chemokine processing by proteases is emerging as an important regulatory mechanism of leukocyte functions and possibly also of cancer progression. We screened a large panel of chemokines for degradation by cathepsins B and D, two proteases involved in tumor progression. Among the few substrates processed by both proteases, we focused on CCL20, the unique chemokine ligand of CCR6 that is expressed on immature dendritic cells and subtypes of memory lymphocytes. Analysis of the cleavage sites demonstrate that cathepsin B specifically cleaves off four C-terminally located amino acids and generates a CCL20_1–66 isoform with full functional activity. By contrast, cathepsin D totally inactivates the chemotactic potency of CCL20 by generating CCL20_1–55, CCL20_1–52, and a 12-aa C-terminal peptide CCL20_59–70. Proteolytic cleavage of CCL20 occurs also with chemokine bound to glycosaminoglycans. In addition, we characterized human melanoma cells as a novel CCL20 source and as cathepsin producers. CCL20 production was up-regulated by IL-1 and TNF- in all cell lines tested, and in human metastatic melanoma cells. Whereas cathepsin D is secreted in the extracellular milieu, cathepsin B activity is confined to cytosol and cellular membranes. Our studies suggest that CCL20 processing in the extracellular environment of melanoma cells is exclusively mediated by cathepsin D. Thus, we propose a model where cathepsin D inactivates CCL20 and possibly prevents the establishment of an effective antitumoral immune response in melanomas.

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