University of Dundee

Dr. Ignacio Moraga Gonzalez

Position: 
Principal Investigator
Address: 
School of Life Sciences, University of Dundee, Dundee
Full Telephone: 
+44 (0) 1382 386793 , int ext
Email: 

Research

The primary research interest of the lab is to understand the cellular and molecular mechanisms determining the specificity of signalling activated by cytokine and their receptors. 

Cytokines are a large family of soluble messengers, whose main function is to oversee the correct functioning of the immune system and represent a paradigm for differential signal activation. In response to environmental changes cells secrete cytokines, which in turn act on immune cells and determine the nature, potency and duration of the immune response. 

A unique feature of cytokines is their large functional pleiotropy. Cytokines elicit a wide range of bioactivities over a large subset of responsive cells, which often result in severe toxicity when agonitic cytokine therapies are implemented into the clinic. In order to rationally manipulate cytokine responses, which could fundamentally change the way that we currently treat human diseases, first we need a systematic understanding of how signaling is initiated and propagated by cytokines. 

To date, how a cytokine-cytokine receptor complex generates signalling specificity and how that initial signalling quantum event generated upon ligand binding is transmitted across the intracellular signalling networks to produce biological activities remains very poorly defined. Our current work combines protein engineering, combinatorial biology, mass spectrometry and structural biology to a) identify the signaling networks engaged by key immunomodulatory cytokines across different immune cell subsets (i.e. CD4 and CD8 T cells, B cells, macrophages,…) and b) manipulate cytokine responses to better treat immune disorders via engineering of cytokine surrogate ligands with tailored activities.

 

 

Publications

Spangler JB, Moraga I, Jude KM, Savvides CS, Garcia KC. 2019 Sep. A strategy for the selection of monovalent antibodies that span protein dimer interfaces. J Biol Chem. 20;294(38):13876-13886. doi: 10.1074/jbc.RA119.009213.

Martinez-Fabregas J, Wilmes S, Wang L, Hafer M, Pohler E, Lokau J, Garbers C, Cozzani A, Piehler J, Kazemian M, Mitra S, Moraga Gonzalez I. 2019. Kinetics of cytokine receptor trafficking determine signaling and functional selectivity. eLife. 8:1-32. https://doi.org/10.7554/eLife.49314

Chen Y, Vandereyken M, Newton I, Moraga Gonzalez I, Nathke I, Swamy M. 2019. Loss of Adenomatous polyposis coli function renders intestinal epithelial cells resistant to the cytokine IL-22. PLoS Biology. 17(11):1-23. https://doi.org/10.1371/journal.pbio.3000540

Gorby C, Martinez-Fabregas J, Wilmes S, Moraga Gonzalez I. 2018. Mapping determinants of cytokine signaling via protein engineering. Frontiers in Immunology. 9. https://doi.org/10.3389/fimmu.2018.02143

Moraga, I., Spangler, J. B., Mendoza, J. L., Gakovic, M., Wehrman, T. S., Krutzik, P. and Garcia, K. C. (2017) Synthekines are surrogate cytokine and growth factor agonists that compel signaling through non-natural receptor dimers. eLife. 6d.o.i 10.7554/eLife.22882

Mendoza, J. L., Schneider, W. M., Hoffmann, H. H., Vercauteren, K., Jude, K. M., Xiong, A., Moraga, I., Horton, T. M., Glenn, J. S., de Jong, Y. P., Rice, C. M. and Garcia, K. C. (2017) The IFN-lambda-IFN-lambdaR1-IL-10Rbeta Complex Reveals Structural Features Underlying Type III IFN Functional Plasticity. Immunity. 46, 379-392 d.o.i 10.1016/j.immuni.2017.02.017

Kim, A. R., Ulirsch, J. C., Wilmes, S., Unal, E., Moraga, I., Karakukcu, M., Yuan, D., Kazerounian, S., Abdulhay, N. J., King, D. S., Gupta, N., Gabriel, S. B., Lander, E. S., Patiroglu, T., Ozcan, A., Ozdemir, M. A., Garcia, K. C., Piehler, J., Gazda, H. T., Klein, D. E. and Sankaran, V. G. (2017) Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation. Cell. 168, 1053-1064 e1015. d.o.i 10.1016/j.cell.2017.02.026

Ho, C. C., Chhabra, A., Starkl, P., Schnorr, P. J., Wilmes, S., Moraga, I., Kwon, H. S., Gaudenzio, N., Sibilano, R., Wehrman, T. S., Gakovic, M., Sockolosky, J. T., Tiffany, M. R., Ring, A. M., Piehler, J., Weissman, I. L., Galli, S. J., Shizuru, J. A. and Garcia, K. C. (2017) Decoupling the Functional Pleiotropy of Stem Cell Factor by Tuning c-Kit Signaling. Cell. 168, 1041-1052 e1018. d.o.i10.1016/j.cell.2017.02.011

You, C., Marquez-Lago, T. T., Richter, C. P., Wilmes, S., Moraga, I., Garcia, K. C., Leier, A. and Piehler, J. (2016) Receptor dimer stabilization by hierarchical plasma membrane microcompartments regulates cytokine signaling. Science advances. 2, e1600452 d.o.i 10.1126/sciadv.1600452

Moraga, I., Wernig, G., Wilmes, S., Gryshkova, V., Richter, C. P., Hong, W. J., Sinha, R., Guo, F., Fabionar, H., Wehrman, T. S., Krutzik, P., Demharter, S., Plo, I., Weissman, I. L., Minary, P., Majeti, R., Constantinescu, S. N., Piehler, J. and Garcia, K. C. (2015) Tuning cytokine receptor signaling by re-orienting dimer geometry with surrogate ligands. Cell. 160, 1196-1208 d.o.i10.1016/j.cell.2015.02.011

Moraga, I., Richter, D., Wilmes, S., Winkelmann, H., Jude, K., Thomas, C., Suhoski, M. M., Engleman, E. G., Piehler, J. and Garcia, K. C. (2015) Instructive roles for cytokine-receptor binding parameters in determining signaling and functional potency. Science signaling. 8, ra114 d.o.i 10.1126/scisignal.aab2677

Ring, A. M., Lin, J. X., Feng, D., Mitra, S., Rickert, M., Bowman, G. R., Pande, V. S., Li, P., Moraga, I., Spolski, R., Ozkan, E., Leonard, W. J. and Garcia, K. C. (2012) Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15. Nature immunology. 13, 1187-1195 d.o.i 10.1038/ni.2449

Junttila, I. S., Creusot, R. J., Moraga, I., Bates, D. L., Wong, M. T., Alonso, M. N., Suhoski, M. M., Lupardus, P., Meier-Schellersheim, M., Engleman, E. G., Utz, P. J., Fathman, C. G., Paul, W. E. and Garcia, K. C. (2012) Redirecting cell-type specific cytokine responses with engineered interleukin-4 superkines. Nature chemical biology. 8, 990-998 d.o.i 10.1038/nchembio.1096

Levin, A. M., Bates, D. L., Ring, A. M., Krieg, C., Lin, J. T., Su, L., Moraga, I., Raeber, M. E., Bowman, G. R., Novick, P., Pande, V. S., Fathman, C. G., Boyman, O. and Garcia, K. C. (2012) Exploiting a natural conformational switch to engineer an interleukin-2 'superkine'. Nature. 484, 529-533 d.o.i 10.1038/nature10975