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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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2015
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| In: |
The journal of immunology
Year: 2015, Volume: 195, Issue: 9, Pages: 4228-4243 |
| ISSN: | 1550-6606 |
| DOI: | 10.4049/jimmunol.1500622 |
| Online Access: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.4049/jimmunol.1500622 Verlag, kostenfrei, Volltext: http://www.jimmunol.org.ezproxy.medma.uni-heidelberg.de/content/195/9/4228 
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| Author Notes: | Francesca Rampoldi, Mahnaz Bonrouhi, Martin E. Boehm, Wolf D. Lehmann, Zoran V. Popovic, Sylvia Kaden, Giuseppina Federico, Fabian Brunk, Hermann-Josef Gröne, and Stefan Porubsky |
| 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. |
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| Item Description: | Gesehen am 09.01.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1550-6606 |
| DOI: | 10.4049/jimmunol.1500622 |