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Aschenbrenner, I.* ; Siebenmorgen, T. ; Lopez, A. ; Parr, M.* ; Ruckgaber, P.* ; Kerle, A.* ; Rührnößl, F.* ; Catici, D.* ; Haslbeck, M.* ; Frishman, D.* ; Sattler, M. ; Zacharias, M.* ; Feige, M.J.*

Assembly-dependent structure formation shapes human interleukin-23 versus interleukin-12 secretion.

J. Mol. Biol. 435:168300 (2023)
Verlagsversion DOI PMC
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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 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
Sprache englisch
Veröffentlichungsjahr 2023
HGF-Berichtsjahr 2023
ISSN (print) / ISBN 0022-2836
e-ISSN 1089-8638
Zeitschrift Journal of Molecular Biology
Quellenangaben Band: 435, Heft: 23, Seiten: , Artikelnummer: 168300 Supplement: ,
Verlag Elsevier
Verlagsort 24-28 Oval Rd, London Nw1 7dx, England
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-503000-001
Förderungen German Research Foundation DFG (Sonderforschungsbereich 1035)
Marianne-Plehn-Program of the Elite Network of Bavaria
German Academic Scholarship Foundation
DOI 10.1016/j.jmb.2023.168300
WOS ID 001105452100001
Scopus ID 85174403855
PubMed ID 37805067
Erfassungsdatum 2023-11-28
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