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G₁₆ Couples Chemoattractant Receptors to NF-B Activation¹

Ming Yang^*, Hairong Sang^*, Arshad Rahman^*, Dianqing Wu, Asrar B. Malik^* and Richard D. Ye^2,*

^* Department of Pharmacology, College of Medicine, University of Illinois, Chicago, IL 60612; and Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT 06030

The guanine nucleotide-binding regulatory protein -subunit, G₁₆, is primarily expressed in hemopoietic cells, and interacts with a large number of seven-membrane span receptors including chemoattractant receptors. We investigated the biological functions resulting from G₁₆ coupling of chemoattractant receptors in a transfected cell model system. HeLa cells expressing a B-driven luciferase reporter, G₁₆, and the formyl peptide receptor responded to fMLP with a 7- to 10-fold increase in luciferase activity. This response was accompanied by phosphorylation of IB and elevation of nuclear B-DNA binding activity, indicating activation of NF-B. In contrast to G₁₆, expression of G_q, G₁₃, and G_i2 resulted in a marginal increase in B luciferase activity. A GTPase-deficient, constitutively active G₁₆ mutant (Q212L) could replace agonist stimulation for activation of NF-B. Furthermore, expression of G₁₆ (Q212L) markedly enhanced TNF--induced B reporter activity. The G₁₆-mediated NF-B activation was paralleled by an increase in phospholipase C- activity, and was blocked by pharmacological inhibitors of protein kinase C (PKC) and by buffering of intracellular Ca²⁺. The involvement of a conventional PKC isoform was confirmed by the finding that expression of PKC enhanced the effect of G₁₆, and a dominant negative PKC partially blocked G₁₆-mediated NF-B activation. In addition to formyl peptide receptor, G₁₆ also enhanced NF-B activation by the C5a and C3a receptors, and by CXC chemokine receptor 2 and CCR8. These results suggest a potential role of G₁₆ in transcriptional regulation downstream of chemoattractant receptors.

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