Protein Translation Control of Cytokine Receptors

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Receptor proteins help cells communicate with their environment. The availability of these proteins can be controlled at three stages, i) where the DNA/genes coding these proteins get converted to mRNA/transcripts (transcriptional control), ii) at the protein synthesis stage (translational control), iii) modification of proteins after synthesis (post-translational modifications). Of these, translational control and its role in complex processes such as immune regulation is under appreciated. Recent work by collaborator J. Dinman (U. Maryland), showed that programmed ribosomal frameshifts (PRF), a mechanism of translational control, occurs in mammalian cells. This is exciting, as PRF had previously only been shown in yeast and virus transcript regulation. In this mechanism, structures called pseudoknot motifs cause the ribosomes to slip backwards on the mRNA during protein synthesis, causing less protein to form. We used immune molecules called cytokines, particularly the Interleukin-7 (IL-7) receptor and its IL-7R subunit, to show that PRF can regulate cytokine receptors and may play a role in the development and functioning of a normal immune system. Interleukin-7 (IL-7) is a cytokine essential for immune development which shows the importance of tight control of receptor and hormone levels. It plays central roles in development of T- and B-cells and innate lymphoid cells. We have proven expertise in working with IL-7, and have already shown that IL-7R signals are critical for T- and B-cell development. Our promising preliminary work on the role of PRF in translational control of IL-7R, raises basic mechanistic questions about how the development of a normal immune system is controlled via translational control of cytokines, addressed in the Aims. Our long-term goal is to address the importance of protein synthesis control in tuning cytokine receptor availability. We hypothesize that motifs in cytokine RNAs confer protein synthesis control that is regulated in T cells. To test this hypothesis we will: 1) investigate how cytokines are translationally regulated by PRF, using IL-7R as a model; 2) assess how such translational control of cytokines is regulated; 3) evaluate other mechanisms of translational control of cytokines, such as initiation. We will use advanced molecular biology methods and established experimental systems in our lab for this work. The results of this research program will provide insight into a new form of regulation in mammalian cells, which in the future can help develop applications in animal husbandry and novel biotechnologies to control protein production, and will be of great academic and economic value. This program will help train two graduate students and one undergraduate student recruited to promote equitable opportunity and training for underrepresented groups as per the UBC Equity and Diversity Strategic Plan.