Proinflammatory proteases liberate a discrete high-affinity functional FPRL1 (CCR12) ligand from CCL23.
Most chemokines have been found to bind to and signal through single or highly related chemokine receptors. However, a single chemokine protein, a processed form of the alternatively spliced CCL23 (CKbeta8/MPIF-1) gene product, potently engages both the "classical" chemokine receptor CCR1, as well as FPRL1, a type of pattern recognition receptor on innate immune cells. However, the mechanism by which the alternative form of CCL23 is processed is unknown. In this study, we show that proteases associated with inflammation cleave CCL23 immediately N-terminal to the 18-residue domain encoded by the alternatively spliced nucleotides, resulting in potent CCR1 and FPRL1 activity. The proteases also cleave CCL23 immediately C-terminal to the inserted domain, producing a typical CC chemokine "body" containing even further-increased CCR1 potency and a released approximately 18-aa peptide with full FPRL1 activity but no activity for CCR1. This peptide, which we term SHAAGtide, is by itself an attractant of monocytes and neutrophils in vitro, recruits leukocytes in vivo, and is 50- to 100-fold more potent than all other natural agents posited to act on FPRL1. The appearance of SHAAGtide appears to be transient, however, as the proinflammatory proteases subsequently cleave within the peptide, abolishing its activity for FPRL1. The sequential activation of a transient FPRL1 ligand and a longer-lived CCR1 ligand within a single chemokine may have important consequences for the development of inflammation or the link between innate and adaptive immunity.
Miao
Zhenhua
Z
ChemoCentryx, Mountain View, CA 94043, USA. zmiao@chenocentryx.com
Premack
Brett A
BA
Wei
Zheng
Z
Wang
Yu
Y
Gerard
Craig
C
Showell
Henry
H
Howard
Maureen
M
Schall
Thomas J
TJ
Berahovich
Robert
R
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000737:chemistry / Q000502:physiology*; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009000:Monocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism* / Q000502:physiology; D010449:Peptide Mapping; D011485:Protein Binding / Q000276:immunology; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology; D017434:Protein Structure, Tertiary; D019707:Receptors, Chemokine / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D044067:Receptors, Lipoxin / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D012697:Serine Endopeptidases / Q000737:chemistry / Q000502:physiology*
C105504:CCL23 protein, human; D019742:Chemokines, CC; C105101:FPR2 protein, human; D018836:Inflammation Mediators; D008024:Ligands; D010446:Peptide Fragments; D019707:Receptors, Chemokine; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C071570:SNF1-related protein kinases; D017346:Protein Serine-Threonine Kinases; D012697:Serine Endopeptidases