The Adaptor Protein SAP Directly Associates with CD3[zeta] Chain and Regulates T Cell Receptor Signaling

• Published in: PloS one 2012-08, Vol.7 (8)
• Main Authors: Proust, Richard, Bertoglio, Jacques, Gesbert, Franck
• Format: Article
• Language: English
• Subjects: Cellular signal transduction; Genetic aspects; Killer cells; Proteins; RNA; T cells
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0043200

Mutations altering the gene encoding the SLAM associated protein (SAP) are responsible for the X-linked lymphoproliferative disease or XLP1. Its absence is correlated with a defective NKT cells development, a decrease in B cell functions and a reduced T cells and NK cells cytotoxic activities, thus leading to an immunodeficiency syndrome. SAP is a small 128 amino-acid long protein that is almost exclusively composed of an SH2 domain. It has been shown to interact with the CD150/SLAM family of receptors, and in a non-canonical manner with SH3 containing proteins such as Fyn, [beta]PIX, PKC[theta] and Nck1. It would thus play the role of a minimal adaptor protein. It has been shown that SAP plays an important function in the activation of T cells through its interaction with the SLAM family of receptors. Therefore SAP defective T cells display a reduced activation of signaling events downstream of the TCR-CD3 complex triggering. In the present work, we evidence that SAP is a direct interactor of the CD3[zeta] chain. This direct interaction occurs through the first ITAM of CD3[zeta], proximal to the membrane. Additionally, we show that, in the context of the TCR-CD3 signaling, an Sh-RNA mediated silencing of SAP is responsible for a decrease of several canonical T cell signaling pathways including Erk, Akt and PLC[gamma]1 and to a reduced induction of IL-2 and IL-4 mRNA. Altogether, we show that SAP plays a central function in the T cell activation processes through a direct association with the CD3 complex.