Regulation of IL-24/IL-20R2 complex formation using photocaged tyrosines and UV light

Abstract

Human interleukin 24 (IL-24) is a multifunctional cytokine that represents an important target for autoimmune diseases and cancer. Since the biological functions of IL-24 depend on interactions with membrane receptors, on-demand regulation of the affinity between IL-24 and its cognate partners offers exciting possibilities in basic research and may have applications in therapy. As a proof-of-concept, we developed a strategy based on recombinant soluble protein variants and genetic code expansion technology to photocontrol the binding between IL-24 and one of its receptors, IL-20R2. Screening of non-canonical ortho-nitrobenzyl-tyrosine (NBY) residues introduced at several positions in both partners was done by a combination of biophysical and cell signaling assays. We identified one position for installing NBY, tyrosine70 of IL-20R2, which results in clear impairment of heterocomplex assembly in the dark. Irradiation with 365-nm light leads to decaging and reconstitutes the native tyrosine of the receptor that can then associate with IL-24. Photocaged IL-20R2 may be useful for the spatiotemporal control of the JAK/STAT phosphorylation cascade.

Genetically Encoded Lysine Analogues with Differential Light Sensitivity for Activation of Protein Function

“…Steric encumbrance provided by bulky, photolabile protecting groups can be introduced via genetic code expansion to strategically block activity until activation with excellent spatiotemporal control. Several examples of photocaged cysteine, lysine, and tyrosine derivatives have been reported and have been used to control cell signaling, [6] enzyme function, [7] intein splicing, [8] protein subcellular localization, [9,10] and virus-host cell interactions. [11][12][13] Early photocaged UAAs used the o-nitrobenzyl (oNB) group, [14] a favored photocaging moiety in biological systems since cAMP was caged in 1977.…”

Serum IL‐24 combined with CA125 as screening and prognostic biomarkers for NSCLC

“…Because of its structure, chromosomal location, and biochemical properties, IL-24 has been classified as a member of the IL-10 family (Chen et al, 2023). IL-24 is normally restricted to cells of the immune system and melanocytes and selectively induces apoptosis in cancer cells without harming normal cells (Pham et al, 2023). IL-24 binds to currently recognized IL-24 receptor complexes consisting of two sets of heterodimeric chains, IL-20R1/IL20R2 or IL-22R1/IL-20R2 (Smith et al, 2023).…”