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Assembly-induced folding regulates interleukin 12 biogenesis and secretion.
J. Biol. Chem. 292, 8073-8081 (2017)
Verlagsversion Forschungsdaten DOI
Members of the IL-12 family perform essential functions in immunoregulation by connecting innate and adaptive immunity and are emerging therapeutic targets. They are unique among other interleukins in forming heterodimers that arise from extensive subunit sharing within the family, leading to the production of at least four functionally distinct heterodimers from only five subunits. This raises important questions about how the assembly of IL-12 family members is regulated and controlled in the cell. Here, using cell-biological approaches, we have dissected basic principles that underlie the biogenesis of the founding member of the family, IL-12. Within the native IL-12 heterodimer, composed of IL-12 alpha and IL-12 alpha, IL-12 alpha possesses three intramolecular and one intermolecular disulfide bridges. We show that, in isolation, IL-12 alpha fails to form its native structure but, instead, misfolds, forming incorrect disulfide bonds. Co-expression of its beta subunit inhibits misfolding and thus allows secretion of biologically active heterodimeric IL-12. On the basis of these findings, we identified the disulfide bonds in IL-12 alpha that are critical for assembly-induced secretion and biological activity of IL-12 versus misfolding and degradation of IL-12 alpha. Surprisingly, two of the three disulfide bridges in IL-12 alpha are dispensable for IL-12 secretion, stability, and biological activity. Extending our findings, we show that misfolding also occurs for IL-23 alpha, another IL-12 family protein. Our results indicate that assembly-induced folding is key in IL-12 family biogenesis and secretion. The identification of essential disulfide bonds that underlie this process lays the basis for a simplified yet functional IL-12 cytokine.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Cell Stimulatory Factor; Lymphocyte Maturation Factor; Endoplasmic-reticulum; Quality-control; Heterodimeric Cytokine; Il-12 Family; P40 Subunit; T-cells; Heavy-chain; P35 Subunit
ISSN (print) / ISBN 0021-9258
Zeitschrift Journal of Biological Chemistry, The
Quellenangaben Band: 292, Heft: 19, Seiten: 8073-8081
Verlag American Society for Biochemistry and Molecular Biology
Begutachtungsstatus Peer reviewed
Institut(e) Institute for Allergy Research (IAF)