Editors' ChoiceCHEMOKINES

Recycled Receptors Provide an Acid Test for Chemokines

+ See all authors and affiliations

Science's STKE  25 May 2004:
Vol. 2004, Issue 234, pp. tw186
DOI: 10.1126/scisignal.2342004tw186

Chemokines act through GPCRs (heterotrimeric guanine-nucleotide-binding protein-coupled receptors) to stimulate cell signaling pathways mediating leukocyte migration and activation. The D6 chemokine receptor, which does not link to signaling pathways, has been viewed as "silent." Weber et al. compared ligand-receptor interactions involving D6 to those involving the signaling receptor CCR5 (CC-chemokine receptor-5) and found that constitutive recycling and pH-dependent ligand affinity allowed D6 to target chemokines for degradation. HEK 293 cells transfected with D6 or CCR5 showed increased internalization of a radiolabeled ligand (CCL3); however, cell surface expression of D6--unlike that of CCR5--did not decrease. A comparison of total-cell D6 content with surface D6 indicated that the majority of D6 was internal. Moreover, immunofluorescence analysis and green fluorescent protein (GFP) labeling revealed that most D6 was in intracellular vesicles, identified as early or recycling endosomes, whereas most CCR5 was on the cell surface. D6 was internalized and recycled to the cell surface even in the absence of ligand, whereas ligand internalized by D6 became degraded. CCR5 mediated degradation of CCL3 and other ligands more slowly than did D6, and intact ligand could be released from CCR5 cells after addition of unlabeled ligand. Preventing vesicle acidification inhibited degradation in D6 cells and enabled the release of intact ligand (as in CCR5 cells). The pH sensitivity of the two receptors differed: The affinity of D6 for ligand decreased with acidification, whereas that of CCR5 increased. During vesicle acidification, ligand was released from D6 for intracellular degradation, whereas ligand associated with CCR5 could recycle to the cell surface. Thus, D6 appears to function as an efficient mechanism of chemokine destruction, and the authors suggest that this may represent a mechanism to regulate chemokine concentration and thereby to modulate inflammation or to influence chemokine or leukocyte movement into lymphatics.

M. Weber, E. Blair, C. V. Simpson, M. O'Hara, P. E. Blackburn, A. Rot, G. J. Graham, R. J. B. Nibbs, The chemokine receptor D6 constitutively traffics to and from the cell surface to internalize and degrade chemokines. Mol. Biol. Cell 15, 2492-2508 (2004). [Abstract] [Full Text]

Related Content