Abstract
The pleiotropic interleukin-6 (IL-6)-type cytokine oncostatin M (OSM) signals in multiple cell types, affecting processes such as cell differentiation, hematopoiesis, and inflammation. In humans, OSM exerts its effects through activation of either of two different heterodimeric receptor complexes, formed by glycoprotein 130 (gp130) and either OSM receptor (OSMR) or leukemia inhibitory factor receptor (LIFR). In contrast, the mouse OSM orthologue acts mainly through dimers containing OSMR and gp130 and shows limited activity through mouse LIFR. Despite their structural similarity, neither human nor mouse OSM signal through the other species' OSMR. The molecular basis for such species-specific signaling, however, remains poorly understood. To identify key molecular features of OSM that determine receptor activation in humans and mice, we generated chimeric mouse-human cytokines. Replacing regions within binding site III of murine OSM with the human equivalents showed that the cytokine's AB loop was critical for receptor selection. Substitutions of individual amino acids within this region demonstrated that residues Asn-37, Thr-40, and Asp-42 of the murine cytokine were responsible for limited LIFR activation and absence of human OSMR/LIFR signaling. In human OSM, Lys-44 appeared to be the main residue preventing mouse OSMR activation. Our data reveal that individual amino acids within the AB loop of OSM determine species-specific activities. These mutations might reflect a key step in the evolutionary process of this cytokine, in which receptor promiscuity gives way to ligand-receptor specialization.
Highlights
The pleiotropic interleukin-6 (IL-6)–type cytokine oncostatin M (OSM) signals in multiple cell types, affecting processes such as cell differentiation, hematopoiesis, and inflammation
We recently reported the existence of two specific regions within binding site III of human OSM (hOSM), the AB loop and N-terminal helix D, determining hOSMR interaction (24)
A conserved FXXK motif in helix D of OSM is crucial for recognition of both receptors, whereas a small number of amino acids in the AB loop of hOSM were recently found to be key for hOSMR activation (13, 24)
Summary
The AB loop of oncostatin M (OSM) determines species-specific signaling in humans and mice. All studies agree on fundamental differences in cytokine-receptor interactions of human and mouse OSM This fact is further emphasized by the lack of cross-species activity; hOSM signals through murine LIFR but not mouse OSMR, whereas mOSM factor; hLIF and mLIF, human and mouse LIF, respectively; gp130, glycoprotein 130; OSMR, oncostatin M receptor; hOSMR and mOSMR, human and mouse OSMR, respectively; LIFR, leukemia inhibitory factor receptor; hLIFR and mLIFR, human and mouse LIFR, respectively; MAPK, mitogenactivated protein kinase; PI3K/Akt, phosphoinositide 3-kinase/protein kinase B; STAT, signal transducer and activator of transcription; P-STAT, phosphorylated STAT; TIMP1, tissue inhibitor of metalloproteinase 1; BisTris, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol; JNK, c-Jun N-terminal kinase. Our results offer an explanation for the potential evolutionary path of this cytokine, in which the spatial rearrangements that resulted in promiscuous OSMR and LIFR activation (24) are followed by amino acid mutations promoting receptor specialization
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