CD28 costimulatory signal induces protein arginine methylation in T cells

Abstract

Protein phosphorylation initiates signal transduction that triggers lymphocyte activation. However, other posttranslational modifications may contribute to this process. Here, we show that CD28 engagement induced protein arginine methyltransferase activity and methylation on arginine of several proteins, including Vav1. Methylation of Vav1 and IL-2 production were reduced by inhibiting S-adenosyl-L-homocysteine hydrolase, an enzyme that regulates cellular transmethylation. Methylated Vav1 was induced in human and mouse T cells and selectively localized in the nucleus, which suggested that this form marks a nuclear function of Vav1. Our findings uncover a signaling pathway that is controlled by CD28 that is likely to be important for T cell activation.

CD28 co‐signaling in the adaptive immune response

“…Several labs including our own have also reported that CD28 ligation in the absence of TCR engagement can activate NFAT and NFkB activity as well as protein arginine methylation. 88,89,92,118,119 CD28 has long been found to preferentially activate JNK and NFkB, an event that may be accompanied by a unique outcome such as TH2 differentiation. Similarly, P3K activation of numerous PH-domain carrying proteins would cooperate with aspects of TCR signaling.…”

Intracellular Signals of T Cell Costimulation

“…These complexes cooperate with ribosomes assembly chaperone (Rac) signaling pathway downstream effector of Vav and the mitogen-activated kinase kinase 1 (MEKK1), a kinase known to regulate the c-jun N-terminal kinase (JNK) pathway, regulates both NF-κB and the activator protein 1 (AP-1), which controls cytokine secretion (43,45,46). Moreover, Vav-1 plays a key role in the control of NF-κB pathway by targeting IKKα in the T cell membrane and favoring its activation in response to CD28 stimulation (47), which increases protein arginine methyltransferase activity and subsequently promotes the methylation on arginine residues of Vav1 (48). It is also shown that PKC isotypes are not dispensable in the signaling pathway of cytokine production induced by CD28, which recruits PKCθ in immunological synapse and enhances nuclear factor of activated T cells (NF-AT), AP1 translocation that mediates IL-2 secretion (49).…”

Suppressive effects of tumor cell-derived 5′-deoxy-5′-methylthioadenosine on human T cells

“…53 To confirm that MTA exerted indeed an impact on global asymmetric methylation events, stimulated T cells were lysed after distinct periods of time and a Western blot was performed to detect global asymmetric protein methylation. Fig.…”