Synthekines are surrogate cytokine and growth factor agonists that compel signaling through non-natural receptor dimers

Moraga, Ignacio; Spangler, Jamie B.; Mendoza, Juan L.; Gakovic, Milica; Wehrman, Tom S.; Krutzik, Peter O.; García, K. Christopher

doi:10.7554/elife.22882

Cited by 58 publications

(52 citation statements)

References 53 publications

(73 reference statements)

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“…Two recent reports describe surrogate dimeric ligands, which specifically bind and activate natural cytokine receptors supporting our hypothesis that receptor activation might be generally possible by dimeric ligands 34 , 35 . For IL-6 and IL-23 signaling, we used homo- and heterodimeric GFP:mCherry fusion proteins, but we were also able to generate homo- and heterotrimeric GFP:mCherry variants.…”

Section: Discussionsupporting

confidence: 84%

Synthetic cytokine receptors transmit biological signals using artificial ligands

et al. 2018

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Cytokine-induced signal transduction is executed by natural biological switches, which among many others control immune-related processes. Here, we show that synthetic cytokine receptors (SyCyRs) can induce cytokine signaling using non-physiological ligands. High-affinity GFP- and mCherry-nanobodies were fused to transmembrane and intracellular domains of the IL-6/IL-11 and IL-23 cytokine receptors gp130 and IL-12Rβ1/IL-23R, respectively. Homo- and heterodimeric GFP:mCherry fusion proteins as synthetic cytokine-like ligands were able to induce canonical signaling in vitro and in vivo. Using SyCyR ligands, we show that IL-23 receptor homodimerization results in its activation and IL-23-like signal transduction. Moreover, trimeric receptor assembly induces trans-phosphorylation among cytokine receptors with associated Janus kinases. The SyCyR technology allows biochemical analyses of transmembrane receptor signaling in vitro and in vivo, cell-specific activation through SyCyR ligands using transgenic animals and possible therapeutic regimes involving non-physiological targets during immunotherapy.

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Section: Discussionsupporting

confidence: 84%

Synthetic cytokine receptors transmit biological signals using artificial ligands

et al. 2018

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“…Instead, a specific ligand-induced crossed-over or asymmetric TM dimer conformation could trigger switch region binding to the opposing F3 subdomain, and subsequent formation of the JAK2 dimer as we see in our structures. The requirement of a specific TM conformation for maximal JAK activation can also help explain data obtained using receptor dimerization methods such as antibodies ( Li et al, 2013 ; Kai et al, 2008 ; Müller-Newen et al, 2000 ; Zhang et al, 2012 ), peptides ( Livnah et al, 1996 ), diabodies ( Moraga et al, 2015 ; Nakano et al, 2009 ), and engineered cytokines ( Moraga et al, 2017 ; Rafei et al, 2007 ). While these non-natural means of dimerization do engage JAK signaling pathways, JAK kinase activity, as measured by receptor or STAT phosphorylation, is rarely induced at the same maximal levels seen for the native ligands.…”

Section: Discussionmentioning

confidence: 98%

“…These findings correlate with studies that show that JAK activation is sensitive, but not entirely disrupted, by changing the juxtamembrane peptide length by adding alanine residues ( Constantinescu et al, 2001 ; Greiser et al, 2002 ). Atypical TM conformations produced using surrogate dimerizing agents could plausibly alter the structure and kinetics of JAK dimer formation, producing unique levels of JAK activation and varied downstream signaling outputs ( Moraga et al, 2015 , 2017 ; Syed et al, 1998 ).…”

Section: Discussionmentioning

confidence: 99%

Receptor-mediated dimerization of JAK2 FERM domains is required for JAK2 activation

Ferrao¹,

Wallweber²,

Lupardus³

2018

eLife

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Cytokines and interferons initiate intracellular signaling via receptor dimerization and activation of Janus kinases (JAKs). How JAKs structurally respond to changes in receptor conformation induced by ligand binding is not known. Here, we present two crystal structures of the human JAK2 FERM and SH2 domains bound to Leptin receptor (LEPR) and Erythropoietin receptor (EPOR), which identify a novel dimeric conformation for JAK2. This 2:2 JAK2/receptor dimer, observed in both structures, identifies a previously uncharacterized receptor interaction essential to dimer formation that is mediated by a membrane-proximal peptide motif called the ‘switch’ region. Mutation of the receptor switch region disrupts STAT phosphorylation but does not affect JAK2 binding, indicating that receptor-mediated formation of the JAK2 FERM dimer is required for kinase activation. These data uncover the structural and molecular basis for how a cytokine-bound active receptor dimer brings together two JAK2 molecules to stimulate JAK2 kinase activity.

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“…For instance, in cancer types where TSLP might be tumor-protective, recombinant TSLP could prove to have therapeutic value either independently, or in the form of an immunocytokine fusion for tumor suppression by analogy to IL-2 ( 219 , 220 ). Leveraging on the available structural data on the TSLP-receptor complex together with diverse display techniques to select hits with tailored characteristics could be considered in the design of TSLP antagonists or agonists ( 115 , 221 , 222 ).…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

Modulation of Signaling Mediated by TSLP and IL-7 in Inflammation, Autoimmune Diseases, and Cancer

Marković

Savvides

2020

Front. Immunol.

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Thymic Stromal Lymphopoietin (TSLP) and Interleukin-7 (IL-7) are widely studied cytokines within distinct branches of immunology. On one hand, TSLP is crucially important for mediating type 2 immunity at barrier surfaces and has been linked to widespread allergic and inflammatory diseases of the airways, skin, and gut. On the other hand, IL-7 operates at the foundations of T-cell and innate lymphoid cell (ILC) development and homeostasis and has been associated with cancer. Yet, TSLP and IL-7 are united by key commonalities in their structure and the structural basis of the receptor assemblies they mediate to initiate cellular signaling, in particular their cross-utilization of IL-7Rα. As therapeutic targeting of TSLP and IL-7 via diverse approaches is reaching advanced stages and in light of the plethora of mechanistic and structural data on receptor signaling mediated by the two cytokines, the time is ripe to provide integrated views of such knowledge. Here, we first discuss the major pathophysiological roles of TSLP and IL-7 in autoimmune diseases, inflammation and cancer. Subsequently, we curate structural and mechanistic knowledge about receptor assemblies mediated by the two cytokines. Finally, we review therapeutic avenues targeting TSLP and IL-7 signaling. We envision that such integrated view of the mechanism, structure, and modulation of signaling assemblies mediated by TSLP and IL-7 will enhance and fine-tune the development of more effective and selective approaches to further interrogate the role of TSLP and IL-7 in physiology and disease.

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Synthekines are surrogate cytokine and growth factor agonists that compel signaling through non-natural receptor dimers

Cited by 58 publications

References 53 publications

Synthetic cytokine receptors transmit biological signals using artificial ligands

Synthetic cytokine receptors transmit biological signals using artificial ligands

Receptor-mediated dimerization of JAK2 FERM domains is required for JAK2 activation

Modulation of Signaling Mediated by TSLP and IL-7 in Inflammation, Autoimmune Diseases, and Cancer

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