Lymphocyte Cell Biology Unit, Department of Immunology, Imagopole, Institut Pasteur, F-75015 Paris, Cedex 15, France.
J Cell Biol. 2011 Nov 28;195(5):839-53. doi: 10.1083/jcb.201103105. Epub 2011 Nov 21.
Antigen recognition within immunological synapses triggers and sustains T cell activation by nucleating protein microclusters that gather T cell receptors (TCRs), kinases, and adaptors. Dissipation of these microclusters results in signal termination, but how this process is regulated is unclear. In this paper, we reveal that release of the adaptors SLP76 and GADS from signaling microclusters is induced by the serine/threonine protein kinase HPK1 and that phosphorylation of GADS plays a major role in this process. We found that HPK1 was recruited into microclusters and triggered their dissipation by inducing the phosphorylation of a threonine-containing motif of GADS, together with the previously described serine phosphorylation of SLP76. These events induced the cooperative binding of 14-3-3 proteins to SLP76-GADS complexes, leading to their uncoupling from the transmembrane adaptor LAT and consequently reducing microcluster persistence and activation-induced gene transcription. These results demonstrate that serine/threonine phosphorylation of multiple TCR-proximal effectors controls the stability of signaling microclusters, thereby determining the intensity of T cell responses.
免疫突触内的抗原识别通过形成募集 T 细胞受体 (TCR)、激酶和衔接蛋白的蛋白微簇触发并维持 T 细胞激活。这些微簇的消散会导致信号终止，但这个过程如何被调节尚不清楚。在本文中，我们揭示了衔接蛋白 SLP76 和 GADS 从信号微簇中的释放是由丝氨酸/苏氨酸蛋白激酶 HPK1 诱导的，并且 GADS 的磷酸化在这个过程中起着主要作用。我们发现 HPK1 被募集到微簇中，并通过诱导 GADS 中含有苏氨酸的基序的磷酸化以及先前描述的 SLP76 的丝氨酸磷酸化，触发了它们的消散。这些事件诱导了 14-3-3 蛋白与 SLP76-GADS 复合物的协同结合，导致它们与跨膜衔接蛋白 LAT 解偶联，从而减少微簇的持久性和激活诱导的基因转录。这些结果表明，多个 TCR 近端效应物的丝氨酸/苏氨酸磷酸化控制着信号微簇的稳定性，从而决定了 T 细胞反应的强度。
