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University. Rewiring cytokine receptors for custom cellular responses Rachel Hsu, Emily Mesev, Payam Farahani, Jared Toettcher Engineered cell-based therapies are a rapidly advancing technology that have much potential in treating a wide range of diseases. However, strategies for optimizing synthetic receptors as tools to tailor cellular outputs to customized inputs are urgently needed. Here, we propose a receptor biosensor platform based on cytokine receptors. Cytokine receptors use the simple, compact Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway and thus provide much flexibility and can be used as a model to understand possibilities for synthetic receptors. We investigated the modularity of cytokine receptors as a synthetic platform by reprogramming type I and type III interferon (IFN) receptors to phosphorylate alternative STATs and novel substrates that can trigger user-defined responses. Preliminary findings indicate that cytokine receptors can be modified to sense other molecules, such as erythropoietin (EPO), and activate different substrates, including a phosphorylated tyrosine tag (pYtag) in the form of an immune tyrosine activation motif (ITAM). Activation of this pYtag triggers the recruitment of a cognate tandem-SH2 domain that can be conjugated to a fluorophore for detection. We further developed the IFN biosensor system design to trigger cleavage by a protease, which can potentially induce the nuclear localization of user-specified transcription factors. By implementing these receptors in human embryonic kidney 293 cells, we hope to create customized biological functions. This could potentially be a powerful tool for developing better synthetic signaling platforms and could have many therapeutic applications.

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Princeton

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