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An Interspecies Analysis Reveals Molecular Construction Principles of Interleukin 27

Müller, Stephanie I., Aschenbrenner, Isabel, Zacharias, Martin, Feige, Matthias J.
Journal of molecular biology 2019 v.431 no.12 pp. 2383-2393
biogenesis, dimerization, disulfide bonds, humans, immunomodulation, inflammation, interleukins, mice
Interleukin 27 (IL-27) is a cytokine that regulates inflammatory responses. It is composed of an α subunit (IL-27α) and a β subunit (EBI3), which together form heterodimeric IL-27. Despite this general principle, IL-27 from different species shows distinct characteristics: Human IL-27α is not secreted autonomously while EBI3 is. In mice, the subunits show a reciprocal behavior. The molecular basis and the evolutionary conservation of these differences have remained unclear. They are biologically important, however, since secreted IL-27 subunits can act as cytokines on their own.Here, we show that formation of a single disulfide bond is an evolutionary conserved trait, which determines secretion-competency of IL-27α. Furthermore, combining cell-biological with computational approaches, we provide detailed structural insights into IL-27 heterodimerization and find that it relies on a conserved interface. Lastly, our study reveals a hitherto unknown construction principle of IL-27: one secretion-competent subunit generally pairs with one that depends on the other to induce its secretion.Taken together, these findings significantly extend our understanding of IL-27 biogenesis as a key cytokine and highlight how protein assembly can influence immunoregulation.