Title: Recognition versus adaptive upregulation and degradation of CC chemokines by the chemokine decoy receptor D6 are determined by their N-terminal sequence
Authors: Savino, Benedetta ×
Borroni, Elena Monica
Machado Torres, Nina
Proost, Paul
Struyf, Sofie
Mortier, Anneleen
Mantovani, Alberto
Locati, Massimo
Bonecchi, Raffaella #
Issue Date: Sep-2009
Publisher: American Society for Biochemistry and Molecular Biology
Series Title: Journal of Biological Chemistry vol:284 issue:38 pages:26207-26215
Abstract: The chemokine decoy receptor D6 controls inflammatory responses by selective recognition and degradation of most CCR1 to CCR5 agonistic ligands. CCL14 is a homeostatic chemokine present at high concentrations in the serum with a weak agonist activity on CCR1. Under inflammatory conditions, plasmin and UPA-mediated truncation of 8 amino acids generates the potent CCR1/CCR3/CCR5 isoform CCL14(9-74), which is further processed and inactivated by dipeptidyl peptidase IV/CD26 that generates CCL14(11-74). Here we report that D6 efficiently binds both CCL14 and its truncated isoforms. Like other D6 ligands, the biologically-active CCL14(9-74) induces adaptive upregulation of D6 expression on the cell membrane, and is rapidly and efficiently degraded. In contrast, the D6-mediated degradation of the biologically-inactive isoforms CCL14(1-74) and CCL14(11-74) is very inefficient. Thus, D6 cooperates with CD26 in the negative regulation of CCL14 by the selective degradation of its biologically-active isoform. Analysis of a panel of CC chemokines and their truncated isoforms revealed that D6-mediated chemokine degradation does not correlate with binding affinity. Conversely degradation efficiency is positively correlated with D6 adaptive upregulation. Sequence analysis indicated that a proline residue in position 2 of D6 ligands is dispensable for binding but crucial for D6 adaptive upregulation and efficient degradation.
ISSN: 0021-9258
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Molecular Immunology (Rega Institute)
× corresponding author
# (joint) last author

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