title: Molecular mechanisms for viral mimicry of a human cytokine: activation of gp130 by HHV-8 interleukin-6.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV, or HHV-8) encodes a pathogenic viral homologue of human interleukin-6 (IL-6). In contrast to human IL-6 (hIL-6), viral IL-6 (vIL-6) binds directly to, and activates, the shared human cytokine signaling receptor gp130 without the requirement for pre-complexation to a specific alpha-receptor. Here, we dissect the biochemical and functional basis of vIL-6 mimicry of hIL-6. We find that, in addition to the "alpha-receptor-independent" tetrameric vIL-6/gp130 complex, the viral cytokine can engage the human alpha-receptor (IL-6Ralpha) to form a hexameric vIL-6/IL-6Ralpha/gp130 complex with enhanced signaling potency. In contrast to the assembly sequence of the hIL-6 hexamer, the preformed vIL-6/gp130 tetramer can be decorated with IL-6Ralpha, post facto, in a "vIL-6-dependent" fashion. A detailed comparison of the viral and human cytokine/gp130 interfaces indicates that vIL-6 has evolved a unique molecular strategy to interact with gp130, as revealed by an almost entirely divergent structural makeup of its receptor binding sites. Viral IL-6 appears to utilize an elegant combination of both convergent, and unexpectedly divergent, molecular strategies to oligomerize gp130 and activate similar downstream signaling cascades as its human counterpart.
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Fairchild D319, 299 Campus Drive, Stanford, CA 94305-5124, USA.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Boulanger
authors.forename: Dar-chone
authors.initials: DC
authors.lastname: Chow
authors.forename: Elena
authors.initials: E
authors.lastname: Brevnova
authors.forename: Monika
authors.initials: M
authors.lastname: Martick
authors.forename: Gordon
authors.initials: G
authors.lastname: Sandford
authors.forename: John
authors.initials: J
authors.lastname: Nicholas
authors.forename: K Christopher
authors.initials: KC
authors.lastname: Garcia
mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism*; D050822:Cytokine Receptor gp130; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D011485:Protein Binding; D019947:Receptors, Interleukin-6 / Q000502:physiology*; D012514:Sarcoma, Kaposi; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C494199:IL6ST protein, human; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D019947:Receptors, Interleukin-6; D014764:Viral Proteins; C113250:interleukin-6 receptor alpha; D050822:Cytokine Receptor gp130