부산대학교 도서관

Open reading frame 74 (ORF74) of many γ2-herpesviruses encodes a CXC chemokine receptor. The molecular pharmacological profile of ORF74 from herpesvirus saimiri, ECRF3, is characterized here and compared with that of the well known ORF74 from human herpesvirus 8 (HHV8). The ECRF3 receptor bound the so-called ELR (Glu-Leu-Arg) CXC chemokines 125I-CXCL1/GROα, 125I-CXCL6/GCP-2, and 125I-CXCL8/interleukin-8 with high affinity; but in contrast to ORF74 from HHV8, it did not bind the non-ELR CXC chemokine 125I-CXCL10/IP10. Interestingly, the Bmax value for CXCL6/GCP-2 was 3-fold higher than the capacity for maximal binding of CXCL1/GROα to ECRF3 and 85-fold higher than that of CXCL8/interleukin-8, despite similar affinities. Like ORF74 from HHV8, ECRF3 activated a broad range of pathways (Gq, Gi, and G12/13 as well as the cAMP response element-binding protein, NF-κB, NFAT, and serum response element transcription factors) in a ligandregulated manner, with CXCL6/GCP-2 being the most potent and efficacious agonist. ECRF3 signaled constitutively through Gi and G12/13, but surprisingly not through Gq. At the level of transcription factor activation, the serum response element was activated constitutively by ECRF3, whereas cAMP response element-bindlng protein, NFAT, and NF-κB were only ligand-regulated. The maximal signaling capacities were similar for the two receptors; however, the ligand-regulated signaling was responsible for the major part of the total ECRF3 signaling and only for a minor part of the total HHV8 ORF74 signaling. The activation pattern of ECRF3 with constitutive activation of some (but not all) of the employed pathways has not been seen before in endogenous or virus-encoded chemokine receptors. The results suggest that the unique ligand selectivity of ECRF3 among ORF74 receptors could reflect differences in the cellular tropism of the γ2-herpesviruses. [ABSTRACT FROM AUTHOR]