An Interspecies Analysis Reveals Molecular Construction Principles of Interleukin 27. Issue 12 (31st May 2019)

• Record Type: Journal Article
• Authors: Müller, Stephanie I.; Aschenbrenner, Isabel; Zacharias, Martin; Feige, Matthias J.
• Is Part Of: Journal of molecular biology. Volume 431:Issue 12(2019)
• Page Start: 2383
• Page End: 2393
• Publication Date: 2019-05-31
• Subjects: Interleukins -- Protein assembly -- Protein docking -- Protein evolution; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2019.04.032
• Languages: English
• ISSNs: 0022-2836

Abstract

Abstract: 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. Graphical Abstract: Unlabelled Image Highlights: Interleukin 27 (IL-27) is a heterodimeric cytokine that regulates inflammation Disulfide bond formation determines secretion-competency of the IL-27 α subunit In IL-27 from different species either the α or the β subunit can be secreted autonomously Mutagenesis-guided docking provides detailed insights into IL-27 heterodimerization Our study defines molecular construction principles of IL-27