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Reitberger, S.* ; Hammerl, P. ; Aschenbrenner, I.* ; Esser-von Bieren, J. ; Feige, M.J.*

Assembly-induced folding regulates interleukin 12 biogenesis and secretion.

J. Biol. Chem. 292, 8073-8081 (2017)
Publ. Version/Full Text Research data DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords 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
e-ISSN 1083-351X
Journal Journal of Biological Chemistry, The
Quellenangaben Volume: 292, Issue: 19, Pages: 8073-8081 Article Number: , Supplement: ,
Publisher American Society for Biochemistry and Molecular Biology
Publishing Place Bethesda
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute for Allergy Research (IAF)