title: Immunosuppression and Aberrant T Cell Development in the Absence of N-Myristoylation.
abstract: N-myristoylation refers to the attachment of myristic acid to the N-terminal glycine of proteins and substantially affects their intracellular targeting and functions. The thymus represents an organ with a prominent N-myristoylation activity. To elucidate the role of protein N-myristoylation for thymocyte development, we generated mice with a T cell lineage-specific deficiency in N-myristoyl transferase (Nmt)1 and 2. Depletion of Nmt activity in T cells led to a defective transmission of TCR signals, a developmental blockage of thymocytes at the transition from double-negative 3 to 4 stages, and a reduction of all the following stages. We could demonstrate that Lck and myristoylated alanine-rich C kinase substrate, two main myristoylated kinases in T cells, were mislocalized in the absence of Nmt activity. N-myristoylation was also indispensable for early and distal TCR signaling events such as CD3ζ, Zap70, and Erk activation and for release of cytokines such as IFN-γ and IL-2. As a consequence, the initiation and propagation of the TCR signaling cascade was severely impaired. Furthermore, we showed that the absence of myristoylation had an immunosuppressive effect on T cells in vivo after treatment with CpG and stimulation of the TCR with the staphylococcal enterotoxin B superantigen. Therefore, protein myristoylation is indispensable in T cell development and activation and its inhibition might offer a novel strategy to achieve immunosuppression.
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, 69120 Heidelberg, Germany;
authors.forename: Francesca
authors.initials: F
authors.lastname: Rampoldi
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, 69120 Heidelberg, Germany;
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Bonrouhi
authors.affiliation: Molecular Structure Analysis, German Cancer Research Center, 69120 Heidelberg, Germany;
authors.forename: Martin E
authors.initials: ME
authors.lastname: Boehm
authors.affiliation: Molecular Structure Analysis, German Cancer Research Center, 69120 Heidelberg, Germany;
authors.forename: Wolf D
authors.initials: WD
authors.lastname: Lehmann
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, 69120 Heidelberg, Germany; Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, 68135 Mannheim, Germany; and.
authors.forename: Zoran V
authors.initials: ZV
authors.lastname: Popovic
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, 69120 Heidelberg, Germany;
authors.forename: Sylvia
authors.initials: S
authors.lastname: Kaden
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, 69120 Heidelberg, Germany;
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Federico
authors.affiliation: Division of Developmental Immunology, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Brunk
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, 69120 Heidelberg, Germany; h.-j.groene@dkfz.de s.porubsky@dkfz.de.
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, 69120 Heidelberg, Germany; Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, 68135 Mannheim, Germany; and h.-j.groene@dkfz.de s.porubsky@dkfz.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Porubsky
mesh_terms: D000217:Acyltransferases / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D015704:CD4 Antigens / Q000032:analysis; D002478:Cells, Cultured; D007108:Immune Tolerance; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000032:analysis; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D019814:Myristic Acid / Q000378:metabolism*; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D011506:Proteins / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; D019814:Myristic Acid; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D000217:Acyltransferases; C527098:N-myristoyltransferase, mouse; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)