期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 284, 期 38, 页码 26207-26215出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.029249
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资金
- European Community [518167]
- Ministero dell'Istruzione dell'Universita e della Ricerca [2002061255, 2007ENYMAN_003]
- Fondo per gli Investimenti della Ricerca di Base [RBIN04EKCX]
- Fondazione Cariplo
- Centers of Excellence [EF/05/15]
- Concerted Research Actions of the Regional Government of Flanders
- Fund for Scientific Research of Flanders (FWO-Vlaanderen)
- Interuniversity Attraction Poles Programme, Belgian State, Belgian Science Policy
- Fondazione Humanitas per la Ricerca
- Italian Association for Cancer Research
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.
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