Natural truncation of the chemokine MIP-1 beta /CCL4 affects receptor specificity but not anti-HIV-1 activity.
Activated lymphocytes synthesize and secrete substantial amounts of the beta-chemokines macrophage inflammatory protein (MIP)-1 alpha/CCL3 and MIP-1 beta/CCL4, both of which inhibit infection of cells with human immunodeficiency virus type 1 (HIV-1). The native form of MIP-1 beta secreted by activated human peripheral blood lymphocytes (MIP-1 beta(3-69)) lacks the two NH(2)-terminal amino acids of the full-length protein. This truncated form of MIP-1 beta has now been affinity-purified from the culture supernatant of such cells, and its structure has been confirmed by mass spectrometry. Functional studies of the purified protein revealed that MIP-1 beta(3-69) retains the abilities to induce down-modulation of surface expression of the chemokine receptor CCR5 and to inhibit the CCR5-mediated entry of HIV-1 in T cells. Characterization of the chemokine receptor specificity of MIP-1 beta(3-69) showed that the truncated protein not only shares the ability of intact MIP-1 beta to induce Ca(2+) signaling through CCR5, but unlike the full-length protein, it also triggers a Ca(2+) response via CCR1 and CCR2b. These results demonstrate that NH(2)-terminally truncated MIP-1 beta functions as a chemokine agonist with expanded receptor reactivity, which may represent an important mechanism for regulation of immune cell recruitment during inflammatory and antiviral responses.
Guan
Ennan
E
Division of Therapeutic Proteins, CBER, Food and Drug Administration, Bethesda, Maryland 20892, USA. guan@cber.fda.gov
Wang
Jinhai
J
Roderiquez
Gregory
G
Norcross
Michael A
MA
D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054410:Chemokine CCL7; D016207:Cytokines; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation; D019402:Macrophage Inflammatory Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D018945:Monocyte Chemoattractant Proteins / Q000502:physiology; D016133:Polymerase Chain Reaction; D019707:Receptors, Chemokine / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D017384:Sequence Deletion; D013379:Substrate Specificity
C515450:CCL7 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054410:Chemokine CCL7; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; D018945:Monocyte Chemoattractant Proteins; D019707:Receptors, Chemokine; D011994:Recombinant Proteins