Dr. Ignacio Moraga Gonzalez
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
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
Pubmed: 5429090
PMC: 28498099
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
PMC: 28329704
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
Pubmed: 5376096
PMC: 28283061
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.i 10.1016/j.cell.2017.02.011
PMC: 28283060
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
Pubmed: 5135388
PMC: 27957535
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.i 10.1016/j.cell.2015.02.011
Pubmed: 4766813
PMC: 25728669
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
PMC: 26554818
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
Pubmed: 3501574
PMC: 23104097
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
Pubmed: 3508151
PMC: 23103943
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
Pubmed: 3338870
PMC: 22446627