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Open Access Green as soon as Postprint is submitted to ZB.
Assembly-dependent structure formation shapes human interleukin-23 versus interleukin-12 secretion.
J. Mol. Biol. 435:168300 (2023)
Interleukin 12 (IL-12) family cytokines connect the innate and adaptive branches of the immune system and regulate immune responses. A unique characteristic of this family is that each member is anα:βheterodimer. For human αsubunits it has been shown that they depend on theirβsubunit for structure formation and secretion from cells. Since subunits are shared within the family and IL-12 as well as IL-23 use the same βsubunit, subunit competition may influence cytokine secretion and thus downstream immunological functions. Here, we rationally design a folding-competent human IL-23α subunit that does not depend on itsβsubunit for structure formation. This engineered variant still forms a functional heterodimeric cytokine but shows less chaperone dependency and stronger affinity in assembly with its βsubunit. It forms IL-23 more efficiently than its natural counterpart, skewing the balance of IL-12 and IL-23 towards more IL-23 formation. Together, our study shows that folding-competent human IL-12 familyαsubunits are obtainable by only few mutations and compatible with assembly and function of the cytokine. These findings might suggest that human α subunits have evolved for assembly-dependent folding to maintain and regulate correct IL-12 family member ratios in the light of subunit competition.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Chaperones ; Interleukins ; Protein Assembly ; Protein Folding ; Protein Secretion; Il-12 P40 Homodimer; Heterodimeric Cytokine; Endoplasmic-reticulum; Hydrogen-exchange; Natural-killer; Protein; Receptor; Subunit; Family; Il-23
ISSN (print) / ISBN
0022-2836
e-ISSN
1089-8638
Journal
Journal of Molecular Biology
Quellenangaben
Volume: 435,
Issue: 23,
Article Number: 168300
Publisher
Elsevier
Publishing Place
24-28 Oval Rd, London Nw1 7dx, England
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Structural Biology (STB)
Grants
German Research Foundation DFG (Sonderforschungsbereich 1035)
Marianne-Plehn-Program of the Elite Network of Bavaria
German Academic Scholarship Foundation
Marianne-Plehn-Program of the Elite Network of Bavaria
German Academic Scholarship Foundation