Unraveling Viral Interleukin-6 Binding to gp130 and Activation of STAT-Signaling Pathways Independently of the Interleukin-6 Receptor

Abstract

Human herpesvirus 8 encodes a viral version of interleukin-6 (vIL-6) which shows 25% sequence homology with human IL-6. In contrast to human IL-6, which first binds to the IL-6 receptor (IL-6R) and only subsequently associates with the signal transducing receptor subunit gp130, vIL-6 has been shown to directly bind to gp130 without the need of IL-6R. As a functional consequence, vIL-6 can activate far more target cells in the body since all cells express gp130, but only cells such as hepatocytes and some leukocytes express IL-6R. We sought to understand which amino acid sequences within the vIL-6 protein were responsible for its ability to bind and activate gp130 independent of IL-6R. As a first approach, we constructed chimeric IL-6 proteins in which all known gp130 interacting sites (sites II and III) were sequentially transferred from vIL-6 into the human IL-6 protein. To our surprise, human IL-6 carrying all gp130 interacting sites from vIL-6 did not show IL-6R-independent gp130 activation. Even more surprisingly, the loop between helix B and C of vIL-6, clearly shown in the crystal structure not to be in contact with gp130, is indispensable for direct binding to and activation of gp130. This points to an IL-6R induced change of site III conformation in human IL-6, which is already preformed in vIL-6. These data indicate a novel activation mechanism of human IL-6 by the IL-6R that will be important for the construction of novel hyperactive cytokine variants.

Human Herpesvirus 8 Viral Interleukin-6 Signaling through gp130 Promotes Virus Replication in Primary Effusion Lymphoma and Endothelial Cells

“…However, its role in normal virus biology remains unclear. Viral IL-6 and its human IL-6 (hIL-6) homolog share ϳ25% sequence identity, fold into similar three-dimensional structures, and initiate signaling through similar complexes (10)(11)(12)(13)(14)(15). Human IL-6 forms hexameric signaling complexes comprised of two gp80 receptor subunits, two gp130 signal transducers, and two hIL-6 molecules (gp80 2 -gp130 2 -IL-6 2 ) (10).…”

KSHV-induced notch components render endothelial and mural cell characteristics and cell survival

“…It is thus probable that cellular IL-6 induces the Notch components in latency similar to what is observed with lytic phase vIL-6. 35,45 Induction of gp130 has been shown to induce stem cell self-renewal in embryonic cells, 46 whereas many gp130 ligands, such as Gro-␣ 36 and oncostatin M, 34,47 are also expressed in KS cells and function as autocrine and paracrine factors. It is thus possible that gp130 signaling may also expand the KS stem cell population.…”

Castleman's Disease: From Basic Mechanisms to Molecular Therapeutics

“…These oncogenic proteins are characterized by their proangiogenic and antiapoptotic capabilities as well as their ability to activate many important intracellular pathways, particularly the phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR), hypoxia inducible factor (HIF)-␣, and nuclear factor (NF)-B signaling cascades [17,[23][24][25][26][27]. Based on these insights, these pathways may serve, at least theoretically, as targets in the treatment of MCD, even though their use in MCD has never been reported.…”