Immunosuppression and Aberrant T Cell Development in the Absence of N-Myristoylation

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 thy...

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Published in:The Journal of immunology (1950) 2015-11, Vol.195 (9), p.4228-4243
Main Authors: Rampoldi, Francesca, Bonrouhi, Mahnaz, Boehm, Martin E, Lehmann, Wolf D, Popovic, Zoran V, Kaden, Sylvia, Federico, Giuseppina, Brunk, Fabian, Gröne, Hermann-Josef, Porubsky, Stefan
Format: Article
Language:English
Subjects:
Acyltransferases - deficiency
Acyltransferases - physiology
Animals
CD4 Antigens - analysis
Cells, Cultured
Immune Tolerance
Intracellular Signaling Peptides and Proteins - physiology
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - analysis
Membrane Proteins - physiology
Mice
Myristic Acid - metabolism
Myristoylated Alanine-Rich C Kinase Substrate
Proteins - metabolism
Receptors, Antigen, T-Cell - physiology
T-Lymphocytes - immunology
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1500622