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eSymposia | Proteomics in Cell Biology and Disease


Phospho-proteomic Characterization of IL-2 and IL-15 Signaling in Natural Killer Cells


Sep 21, 2020 12:00am ‐ Sep 21, 2020 12:00am

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Phospho-proteomic Characterization of IL-2 and IL-15 Signaling in Natural Killer Cells Abstract: Natural Killer (NK) cells are cytotoxic lymphocytes critical to the innate immune system. Despite their importance in immunology, no studies have characterized how NK cells respond to cytokine stimulation. NK cell proliferation is primarily driven by cytokines, particularly interleukin (IL)-2 and IL-15. Therefore, we performed phospho-proteomic analysis of IL-2 and IL-15 signaling in a model system of NK cells (NK-92). In two independent biological replicates, we identified 4,728 high-confidence phospho-peptides. After 30 minutes of stimulation, analysis revealed that both IL-2 and IL-15 induced significant up-regulation of phosphorylation of Y694 on STAT5 (signal transducer and activator of transcription 5), a phosphorylation site known to be essential to immune cell proliferation. Further analysis with PCA revealed differences between the two cytokines including upregulation of SIPA1 pS74 and RETREG3 pS229 following IL-2 stimulation and upregulation of PRPF3 pS619 and TRIP11 p464 following IL-15 stimulation. Kinase set enrichment analysis (KSEA) revealed several kinases which were differentially activated by IL-2 or IL-15 including Casein Kinase II, Aurora A, and Aurora by IL-2 and GSK-3, ERK1, ERK2, CDK5, PKA, and PKC by IL-15. In addition, time course analysis of NK cells stimulated by either IL-2 or IL-15 for 0, 5, 10, 15, or 30 minutes revealed differential clustering of phospho-peptides, suggesting short-term phosphorylation differences that may contribute to different activation networks. Taken together, these results represent the first phospho-proteomic analysis of NK cells and suggest that the cytokines IL-2 and IL-15 promote NK cell proliferation through different mechanisms. Authors: (presenting author) Melanie A. MacMullan, University of Southern California, Los Angeles, CA, USA, macmulla@usc.edu Pin Wang, University of Southern California, Los Angeles, CA, USA, pinwang@usc.edu Nicholas A. Graham, University of Southern California, Los Angeles, CA, USA, nagraham@usc.edu

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