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RHEUMATOID ARTHRITIS

N-myristoylation of AMPK controls T cell inflammatory function

Nature Immunology volume 20, pages 252–254 (2019)Cite this article

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In patients with rheumatoid arthritis, decreased abundance of the N-myristoyltransferase NMT1 in CD4+ T cells prevents N-myristoylation of the AMP-activated protein kinase AMPK and its localization to the lysosomal membrane, which leads to increased activation of the metabolic checkpoint kinase complex mTORC1 and proinflammatory T cell phenotypes.

N-myristoylation is important in targeting proteins to the surfaces of endomembranes and the plasma membrane. Therefore, this protein modification is of particular importance for the colocalization of signaling proteins to facilitate efficient signal transduction. In T cells, N-myristoylation occurs on various important signaling molecules, including those important in signaling downstream of the T cell antigen receptor (TCR), such as the tyrosine kinases Lck and Fyn1. Studies of mice with T cell–specific deficiency in NMT1 or both NMT1 and NMT2 have shown that N-myristoylation is required for normal T cell development and TCR signaling3. For this reason, the discovery that reduced abundance of NMT1 and protein N-myristoylation is associated with increased differentiation of proinflammatory TH1 and TH17 helper T cells is somewhat surprising. However, the study by Wen et al. provides convincing evidence that NMT1-mediated N-myristoylation controls the inflammatory function of effector T cells2. The data show that NMT1 expression and protein N-myristoylation are decreased in the CD4+ T cells, but not in the CD8+ T cells, found among peripheral blood mononuclear cells (PBMCs) from patients with RA. Interestingly, this finding of reduced abundance of NMT1 in CD4+ T cells appears to be specific to PBMCs from patients with RA, as NMT1 expression is normal in CD4+ T cells from patients with other autoimmune diseases, such as psoriatic arthritis or systemic lupus erythematosus. Also, the effect is specific to NMT1, as NMT2 expression is unchanged in all immune cells analyzed, consistent with the understanding that NMT1 and NMT2 have non-redundant roles1. NMT1 expression in activated CD4+ T cells is found to be inversely correlated with clinical disease activity in patients with RA. Restoring NMT1 expression in CD4+ T cells from patients with RA reduces the differentiation of proinflammatory TH1 and TH17 cells. Conversely, knockdown of NMT1 via small interfering RNA in CD4+ T cells from healthy subjects increases the differentiation of TH1 and TH17 cells.

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Fig. 1: Reduced abundance of NMT1 in CD4+ T cells from patients with RA leads to unrestrained mTORC1 activity.

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  1. School of Biochemistry and Immunology and School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland

    David K. Finlay

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  1. David K. Finlay
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Correspondence to David K. Finlay.

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Finlay, D.K. N-myristoylation of AMPK controls T cell inflammatory function. Nat Immunol 20, 252–254 (2019). https://doi.org/10.1038/s41590-019-0322-4

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