Arginine methylation by a CD28 co-stimulatory signal could be important for the activation of T cells.
The signalling pathways that result in T-cell activation involve post-translational modification of some of the proteins along these pathways. Protein modification by phosphorylation or ubiquitylation has been well documented to be crucial for T-cell activation, but now, in a report published in The Journal of Experimental Medicine, protein arginine methylation has been shown to occur following engagement of the co-stimulatory receptor CD28.
Recent technological advances — for example, in mass spectrometry and proteomics — have indicated that methylation of proteins on arginine residues occurs more often than previously thought. So, Blanchet et al. set out to investigate whether arginine methylation occurs during T-cell activation. Using an antibody specific for methylated arginine, it was shown that the level of arginine methylation was greater in T cells that were stimulated with both superantigen and fibroblast cells engineered to express the CD28 ligand CD80 (5–3.1-B7 cells) than in T cells that were stimulated with superantigen alone. Furthermore, stimulation with 5–3.1-B7 cells alone increased the level of arginine methylation and the level of protein arginine methyltransferase (PRMT) activity more than stimulation with superantigen alone. Consistent with signalling downstream of CD28 ligation having a crucial role in inducing arginine methylation, 5–3.1-B7-cell stimulation of a T-cell line expressing a mutant CD28 molecule that lacks the ability to transmit intracellular signals after ligation could not induce increased PRMT activity.
Further analysis of known effectors of the CD28-signalling pathway indicated that VAV1 was arginine methylated following CD28 engagement and that this depended on CD28 being able to transmit intracellular signals. Arginine-methylated VAV1 was found exclusively in the nuclear fraction of 5–3.1-B7-cell-stimulated T cells. But, following CD28 co-stimulation, the main functions that have so far been described to depend on VAV1 occur in the cytoplasm, so the identification of arginine-methylated VAV1 in the nucleus indicates that VAV1 might have additional functions in T-cell activation: for example, it might modulate the activity of transcription factors.
Further studies are required to determine which T-cell functions are regulated by arginine methylation downstream of CD28 co-stimulation, although initial experiments reported in this paper indicate that this is one mechanism by which T-cell production of interleukin-2 can be regulated. The authors also suggest that, because arginine methylation is a stable protein modification (no enzymes that can remove this modification have been identified so far), arginine methylation downstream of CD28 co-stimulation might contribute to T-cell-fate differentiation decisions.
Karen Honey
References
Blanchet, F., Cardona, A. Letimier, F. A., Hershfield, M. S. & Acuto, O. CD28 costimulatory signal induces protein arginine methylation in T cells. J. Exp. Med.202, 371–377 (2005) | Article | PubMed |
