| First Author | Rampoldi F | Year | 2015 |
| Journal | J Immunol | Volume | 195 |
| Issue | 9 | Pages | 4228-43 |
| PubMed ID | 26423150 | Mgi Jnum | J:226234 |
| Mgi Id | MGI:5696524 | Doi | 10.4049/jimmunol.1500622 |
| Citation | Rampoldi F, et al. (2015) Immunosuppression and Aberrant T Cell Development in the Absence of N-Myristoylation. J Immunol 195(9):4228-43 |
| abstractText | 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 CD3zeta, Zap70, and Erk activation and for release of cytokines such as IFN-gamma 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. |
