title: Recognition versus adaptive up-regulation and degradation of CC chemokines by the chemokine decoy receptor D6 are determined by their N-terminal sequence.
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 up-regulation 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 up-regulation. Sequence analysis indicated that a proline residue in position 2 of D6 ligands is dispensable for binding but crucial for D6 adaptive up-regulation and efficient degradation.
authors.affiliation: Department of Translational Medicine, University of Milan, 20089 Milan, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Savino
authors.forename: Elena Monica
authors.initials: EM
authors.lastname: Borroni
authors.forename: Nina Machado
authors.initials: NM
authors.lastname: Torres
authors.forename: Paul
authors.initials: P
authors.lastname: Proost
authors.forename: Sofie
authors.initials: S
authors.lastname: Struyf
authors.forename: Anneleen
authors.initials: A
authors.lastname: Mortier
authors.forename: Alberto
authors.initials: A
authors.lastname: Mantovani
authors.forename: Massimo
authors.initials: M
authors.lastname: Locati
authors.forename: Raffaella
authors.initials: R
authors.lastname: Bonecchi
mesh_terms: D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D016466:CHO Cells; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D054447:Receptors, CCR10 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*; D000097628:Chemokine Receptor D6
chemical_list: D019742:Chemokines, CC; D018819:Dipeptidyl Peptidase 4; D020033:Protein Isoforms; D054447:Receptors, CCR10; D000097628:Chemokine Receptor D6; C097720:CCL14 protein, human; C042807:DPP4 protein, human