Natural proteolytic processing of hemofiltrate CC chemokine 1 generates a potent CC chemokine receptor (CCR)1 and CCR5 agonist with anti-HIV properties.
Hemofiltrate CC chemokine (HCC)-1 is a recently described human chemokine that is constitutively expressed in numerous tissues and is present at high concentrations in normal plasma. Using a cell line expressing CC chemokine receptor (CCR)5 as a bioassay, we isolated from human hemofiltrate an HCC-1 variant lacking the first eight amino acids. HCC-1[9-74] was a potent agonist of CCR1, CCR3, and CCR5 and promoted calcium flux and chemotaxis of T lymphoblasts, monocytes, and eosinophils. It also blocked entry of HIV-1 strains using CCR5 as coreceptor. Limited tryptic digestion of HCC-1 generated the active variant. Conditioned media from several tumor cell lines activated HCC-1 with a high efficiency, and this activity could be inhibited by serine protease inhibitors. Our results indicate that HCC-1 represents a nonfunctional precursor that can be rapidly converted to the active chemokine by proteolytic processing. This process represents an additional mechanism by which tumor cells might generate chemoattractant molecules and recruit inflammatory cells. It might also affect HIV-1 replication in infected individuals and play an important role in AIDS pathogenesis.
Detheux
M
M
Euroscreen S.A., B-1070 Brussels, Belgium.
Ständker
L
L
Vakili
J
J
Münch
J
J
Forssmann
U
U
Adermann
K
K
Pöhlmann
S
S
Vassart
G
G
Kirchhoff
F
F
Parmentier
M
M
Forssmann
W G
WG
D000328:Adult; D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001681:Biological Assay; D001798:Blood Proteins / Q000378:metabolism*; D020013:Calcium Signaling; D019742:Chemokines, CC / Q000378:metabolism*; D002630:Chemotactic Factors / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte; D017077:Culture Media, Conditioned / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D019713:Receptors, CCR5 / Q000819:agonists*; D019707:Receptors, Chemokine / Q000819:agonists*
D019380:Anti-HIV Agents; D001798:Blood Proteins; C097720:CCL14 protein, human; C515300:CCR1 protein, human; C515350:CCR3 protein, human; D019742:Chemokines, CC; D002630:Chemotactic Factors; D017077:Culture Media, Conditioned; D010446:Peptide Fragments; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D010450:Endopeptidases