The scaffold protein Dlgh1 couples T-cell receptor signaling to activation of the p38 serine/threonine kinase.
Antigenic stimulation of T-cell receptors (TCRs) promotes the activation of a myriad of cytoplasmic signal transduction pathways to affect T cell-mediated adaptive immunity. How a common signal, such as TCR stimulation, activates several discrete signaling networks to promote distinct cellular responses is an area of intense research. In Nature Immunology, Miceli and colleagues report that TCR signaling causes the membrane-associated guanylate kinase (MAGUK) scaffold protein Dlgh1 to bind to and facilitate activation of the p38 serine/threonine kinase, which in turn specifically stimulates NFAT-mediated transcription.
TCR stimulation promotes the recruitment of adaptor and scaffold proteins (including Dlgh1), kinases (including Zap70 and Lck), phospholipases and small GTPases into complexes known as "signalosomes", which coordinate the T cell's response to antigens. p38 is a well known effector of TCR-mediated immune response, and previous work has shown that Lck and Zap70-mediated phosphorylation of p38 is involved in its activation following TCR stimulation. Miceli and colleagues found phosphorylated p38 in complex with Dlgh1 in stimulated T cells. siRNA-mediated depletion of Dlgh1 in stimulated T cells resulted in a decrease in p38 phosphorylation, but had no effect on phosphorylation of Erk or Jnk. NF-κB activity and calcium release were similarly unaffected by Dlgh1 depletion, suggesting that Dlgh1 specifically links TCR signaling to p38 activation.
What, then, are the cellular consequences of this type of p38 activation? Dlgh1 overexpression in stimulated T cells resulted in increased activity of the T cell transcription factor NFAT, but not NF-κB. Pharmacologic inhibition of p38 impaired TCR-induced NFAT transcriptional activity. Furthermore, mutations introduced in the p38 binding domain of Dlgh1 abrogated NFAT phosphorylation and activity, supporting a role for Dlgh1 in coupling TCR signaling to p38 phosphorylation and subsequent NFAT activation. Based on these data, the authors propose a model in which Dlgh1 functions as a scaffold to bring the TCR together with Lck, Zap70 and p38, resulting in p38 activation, NFAT-mediated transcription and T cell response.
Another member of the extensive family of MAGUK scaffold proteins, CARMA1, is involved in the selective activation of Jnk and NF-κB in response to TCR stimulation. It is becoming apparent that these scaffolds, in partnership with associated kinases and phospholipases, play important roles in delineating the "intent" of TCR stimulation.
Emily J. Chenette Signaling Gateway
References
June L. Round, Lisa A. Humphries, Tamar Tomassian, Paul Mittelstadt, Min Zhang & M. Carrie Miceli. Scaffold protein Dlgh1 coordinates alternative p38 kinase activation, directing T cell receptor signals toward NFAT but not NF-κB transcription factors. Nature Immunology8, 154-161 (2007) | Article | PubMed |
Mercedes Rincón & Roger J. Davis. Choreography of MAGUKs during T cell activation. Nature Immunology8, 126-127 (2007) | Article | PubMed |
