Regulation of D6 chemokine scavenging activity by ligand- and Rab11-dependent surface up-regulation.
The decoy receptor D6 plays a nonredundant role in the control of inflammatory processes through scavenging of inflammatory chemokines. However it remains unclear how it is regulated. Here we show that D6 scavenging activity relies on unique trafficking properties. Under resting conditions, D6 constitutively recycled through both a rapid wortmannin (WM)-sensitive and a slower brefeldin A (BFA)-sensitive pathway, maintaining low levels of surface expression that required both Rab4 and Rab11 activities. In contrast to "conventional" chemokine receptors that are down-regulated by cognate ligands, chemokine engagement induced a dose-dependent BFA-sensitive Rab11-dependent D6 re-distribution to the cell membrane and a corresponding increase in chemokine degradation rate. Thus, the energy-expensive constitutive D6 cycling through Rab11 vesicles allows a rapid, ligand concentration-dependent increase of chemokine scavenging activity by receptor redistribution to the plasma membrane. D6 is not regulated at a transcriptional level in a variety of cellular contexts, thus ligand-dependent optimization of its scavenger performance represents a rapid and unique mechanism allowing D6 to control inflammation.
Bonecchi
Raffaella
R
Istituto Clinico Humanitas, Istituti di ricovero e cura a carattere scientifico (IRCCS), Rozzano, Italy. raffaella.bonecchi@humanitas.it
Borroni
Elena M
EM
Anselmo
Achille
A
Doni
Andrea
A
Savino
Benedetta
B
Mirolo
Massimiliano
M
Fabbri
Monica
M
Jala
Venkatakrishna R
VR
Haribabu
Bodduluri
B
Mantovani
Alberto
A
Locati
Massimo
M
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D016166:Free Radical Scavengers; D006801:Humans; D007249:Inflammation; D008024:Ligands; D021381:Protein Transport; D054447:Receptors, CCR10 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D015854:Up-Regulation; D020691:rab GTP-Binding Proteins / Q000502:physiology*; D020695:rab4 GTP-Binding Proteins / Q000502:physiology*; D000097628:Chemokine Receptor D6; D000099193:rab11 GTP-Binding Proteins
D016166:Free Radical Scavengers; D008024:Ligands; D054447:Receptors, CCR10; D020691:rab GTP-Binding Proteins; D020695:rab4 GTP-Binding Proteins; D000097628:Chemokine Receptor D6; D000099193:rab11 GTP-Binding Proteins