PuSH - Publication Server of Helmholtz Zentrum München: Assembly-dependent structure formation shapes human interleukin-23 versus interleukin-12 secretion.

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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)

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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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