Quantitative analysis of how Myc controls T cell proteomes and metabolic pathways during T cell activation
Tóm tắt
T cell expansion and differentiation are critically dependent on the transcription factor c-Myc (Myc). Herein we use quantitative mass-spectrometry to reveal how Myc controls antigen receptor driven cell growth and proteome restructuring in murine T cells. Analysis of copy numbers per cell of >7000 proteins provides new understanding of the selective role of Myc in controlling the protein machinery that govern T cell fate. The data identify both Myc dependent and independent metabolic processes in immune activated T cells. We uncover that a primary function of Myc is to control expression of multiple amino acid transporters and that loss of a single Myc-controlled amino acid transporter effectively phenocopies the impact of Myc deletion. This study provides a comprehensive map of how Myc selectively shapes T cell phenotypes, revealing that Myc induction of amino acid transport is pivotal for subsequent bioenergetic and biosynthetic programs and licences T cell receptor driven proteome reprogramming.
Từ khóa
Tài liệu tham khảo
Araki, 2017, Translation is actively regulated during the differentiation of CD8+ effector T cells, Nature Immunology, 18, 1046, 10.1038/ni.3795
Au-Yeung, 2017, IL-2 modulates the TCR signaling threshold for CD8 but not CD4 T cell proliferation on a Single-Cell level, The Journal of Immunology, 198, 2445, 10.4049/jimmunol.1601453
Chou, 1995, c-Myc is glycosylated at threonine 58, a known phosphorylation site and a mutational hot spot in lymphomas, Journal of Biological Chemistry, 270, 18961, 10.1074/jbc.270.32.18961
Cowling, 2007, The myc transactivation domain promotes global phosphorylation of the RNA polymerase II carboxy-terminal domain independently of direct DNA binding, Molecular and Cellular Biology, 27, 2059, 10.1128/MCB.01828-06
Doherty, 2014, Blocking lactate export by inhibiting the myc target MCT1 disables glycolysis and glutathione synthesis, Cancer Research, 74, 908, 10.1158/0008-5472.CAN-13-2034
Dose, 2009, Intrathymic proliferation wave essential for Valpha14+ natural killer T cell development depends on c-Myc, PNAS, 106, 8641, 10.1073/pnas.0812255106
Geiger, 2016, L-Arginine modulates T cell metabolism and enhances survival and Anti-tumor activity, Cell, 167, 829, 10.1016/j.cell.2016.09.031
Heinzel, 2017, A Myc-dependent division timer complements a cell-death timer to regulate T cell and B cell responses, Nature Immunology, 18, 96, 10.1038/ni.3598
Hosios, 2016, Amino acids rather than glucose account for the majority of cell mass in proliferating mammalian cells, Developmental Cell, 36, 540, 10.1016/j.devcel.2016.02.012
Howden, 2019, Quantitative analysis of T cell proteomes and environmental sensors during T cell differentiation, Nature Immunology, 20, 1542, 10.1038/s41590-019-0495-x
Hughes, 2014, Ultrasensitive proteome analysis using paramagnetic bead technology, Molecular Systems Biology, 10, 10.15252/msb.20145625
Hukelmann, 2016, The cytotoxic T cell proteome and its shaping by the kinase mTOR, Nature Immunology, 17, 104, 10.1038/ni.3314
Lewis, 2018, Replication study: transcriptional amplification in tumor cells with elevated c-Myc, eLife, 7, 10.7554/eLife.30274
Lin, 2012, Transcriptional amplification in tumor cells with elevated c-Myc, Cell, 151, 56, 10.1016/j.cell.2012.08.026
Loftus, 2018, Amino acid-dependent cMyc expression is essential for NK cell metabolic and functional responses in mice, Nature Communications, 9, 10.1038/s41467-018-04719-2
Ly, 2014, A proteomic chronology of gene expression through the cell cycle in human myeloid leukemia cells, eLife, 3, 10.7554/eLife.01630
Mycko, 2009, Selective requirement for c-Myc at an early stage of V(alpha)14i NKT cell development, The Journal of Immunology, 182, 4641, 10.4049/jimmunol.0803394
Nakaya, 2014, Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation, Immunity, 40, 692, 10.1016/j.immuni.2014.04.007
Newsholme, 1985, Glutamine metabolism in lymphocytes: its biochemical, physiological and clinical importance, Quarterly Journal of Experimental Physiology, 70, 473, 10.1113/expphysiol.1985.sp002935
Nie, 2012, c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells, Cell, 151, 68, 10.1016/j.cell.2012.08.033
Osthus, 2000, Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc, Journal of Biological Chemistry, 275, 21797, 10.1074/jbc.C000023200
Preston, 2015, Single cell tuning of myc expression by antigen receptor signal strength and interleukin-2 in T lymphocytes, The EMBO Journal, 34, 2008, 10.15252/embj.201490252
Ricciardi, 2018, The translational machinery of human CD4+ T Cells Is Poised for Activation and Controls the Switch from Quiescence to Metabolic Remodeling, Cell Metabolism, 28, 10.1016/j.cmet.2018.09.010
Richard, 2018, T cell cytolytic capacity is independent of initial stimulation strength, Nature Immunology, 19, 849, 10.1038/s41590-018-0160-9
Ron-Harel, 2016, Mitochondrial biogenesis and proteome remodeling promote One-Carbon metabolism for T cell activation, Cell Metabolism, 24, 104, 10.1016/j.cmet.2016.06.007
Ruggero, 2009, The role of Myc-induced protein synthesis in Cancer, Cancer Research, 69, 8839, 10.1158/0008-5472.CAN-09-1970
Sabò, 2014, Selective transcriptional regulation by myc in cellular growth control and lymphomagenesis, Nature, 511, 488, 10.1038/nature13537
Sinclair, 2013, Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation, Nature Immunology, 14, 500, 10.1038/ni.2556
Sinclair, 2018, Single cell analysis of kynurenine and system L amino acid transport in T cells, Nature Communications, 9, 10.1038/s41467-018-04366-7
Sinclair, 2019, Antigen receptor control of methionine metabolism in T cells, eLife, 8, 10.7554/eLife.44210
Singh, 2019, c-MYC regulates mRNA translation efficiency and start-site selection in lymphoma, The Journal of Experimental Medicine, 216, 1509, 10.1084/jem.20181726
Swamy, 2016, Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy, Nature Immunology, 17, 712, 10.1038/ni.3439
Tan, 2017, Integrative proteomics and phosphoproteomics profiling reveals dynamic signaling networks and bioenergetics pathways underlying T cell activation, Immunity, 46, 488, 10.1016/j.immuni.2017.02.010
Tanner, 2018, Four key steps control glycolytic flux in mammalian cells, Cell Systems, 7, 49, 10.1016/j.cels.2018.06.003
Tesi, 2019, An early Myc-dependent transcriptional program orchestrates cell growth during B-cell activation, EMBO Reports, 20, 10.15252/embr.201947987
Trumpp, 2001, c-Myc regulates mammalian body size by controlling cell number but not cell size, Nature, 414, 768, 10.1038/414768a
Verbist, 2016, Metabolic maintenance of cell asymmetry following division in activated T lymphocytes, Nature, 532, 389, 10.1038/nature17442
Wang, 2011, The transcription factor myc controls metabolic reprogramming upon T lymphocyte activation, Immunity, 35, 871, 10.1016/j.immuni.2011.09.021
Wise, 2008, Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction, PNAS, 105, 18782, 10.1073/pnas.0810199105
Wiśniewski, 2014, A "proteomic ruler" for protein copy number and concentration estimation without spike-in standards, Molecular & Cellular Proteomics, 13, 3497, 10.1074/mcp.M113.037309