Split2 Protein-Ligation Generates Active IL-6-Type Hyper-Cytokines from Inactive Precursors

Jens M. Moll, Melanie Wehmöller, Nils C. Frank, Lisa Homey, Paul Baran, Christoph Garbers, Larissa Lamertz, Jonathan H. Axelrod, Eithan Galun, Henning D. Mootz, Jürgen Scheller*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Trans-signaling of the major pro- and anti-inflammatory cytokines Interleukin (IL)-6 and IL-11 has the unique feature to virtually activate all cells of the body and is critically involved in chronic inflammation and regeneration. Hyper-IL-6 and Hyper-IL-11 are single chain designer trans-signaling cytokines, in which the cytokine and soluble receptor units are trapped in one complex via a flexible peptide linker. Albeit, Hyper-cytokines are essential tools to study trans-signaling in vitro and in vivo, the superior potency of these designer cytokines are accompanied by undesirable stress responses. To enable tailor-made generation of Hyper-cytokines, we developed inactive split-cytokine-precursors adapted for posttranslational reassembly by split-intein mediated protein trans-splicing (PTS). We identified cutting sites within IL-6 (E134/S135) and IL-11 (G116/S117) and obtained inactive split-Hyper-IL-6 and split-Hyper-IL-11 cytokine precursors. After fusion with split-inteins, PTS resulted in reconstitution of active Hyper-cytokines, which were efficiently secreted from transfected cells. Our strategy comprises the development of a background-free cytokine signaling system from reversibly inactivated precursor cytokines.

Original languageAmerican English
Pages (from-to)2260-2272
Number of pages13
JournalACS Synthetic Biology
Issue number12
StatePublished - 15 Dec 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2017 American Chemical Society.


  • IL-11
  • IL-6
  • split-inteins
  • trans-signaling


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