Identification of amino acid residues of gp130 signal transducer and gp80 alpha receptor subunit that are involved in ligand binding and signaling by human herpesvirus 8-encoded interleukin-6.
Human herpesvirus 8-encoded interleukin-6 (vIL-6) signals through the gp130 signal transducer but is not dependent on the IL-6 receptor alpha subunit (IL-6R, gp80) that is required for signaling by endogenous IL-6 proteins; however, IL-6R can enhance vIL-6 activity and can enable signaling through a gp130 variant, gp130.PM5, that is itself unable to support vIL-6 signaling. These findings suggest that the vIL-6-gp130 interactions are qualitatively different from those of human IL-6 (hIL-6) and that vIL-6 signaling may be more promiscuous than that of hIL-6 but that IL-6R may play a role in vIL-6 signaling in vivo. To examine the receptor binding requirements of vIL-6, we have undertaken mutational analyses of regions of gp130 and IL-6R potentially involved in interactions with ligand or in functional complex formation and used these variants in functional, ligand-binding, and receptor dimerization assays. The data presented identify positions within two interstrand loops of the gp130 cytokine-receptor homology domain that are important for vIL-6 signaling and vIL-6-induced receptor dimerization and show that vIL-6, like hIL-6, can form complexes with IL-6R and gp130 but that the roles of putative cytokine-binding residues of IL-6R in ligand-induced functional complex formation are qualitatively different in the case of vIL-6 and hIL-6.
Li
Hong
H
Molecular Virology Laboratories, Department of Oncology, Johns Hopkins University, Baltimore, Maryland 21231, USA.
Nicholas
John
J
D000409:Alanine; D000596:Amino Acids; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002461:Cell Line, Transformed; D050822:Cytokine Receptor gp130; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D000596:Amino Acids; D015703:Antigens, CD; C494199:IL6ST protein, human; D015850:Interleukin-6; D008024:Ligands; D008562:Membrane Glycoproteins; D019947:Receptors, Interleukin-6; C113250:interleukin-6 receptor alpha; D050822:Cytokine Receptor gp130; D000409:Alanine