The adaptor protein SAP directly associates with CD3ζ chain and regulates T cell receptor signaling.
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, βPIX, PKCθ 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 CD3ζ chain. This direct interaction occurs through the first ITAM of CD3ζ, 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 PLCγ1 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.
Institut National de la Santé Et de la Recherche Médicale UMR-S1004, Université Paris-Sud, Hopital Paul Brousse, Villejuif, France.
Richard
R
Proust
Jacques
J
Bertoglio
Franck
F
Gesbert
D026481:Blotting, Far-Western; D015153:Blotting, Western; D017252:CD3 Complex / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear; D008213:Lymphocyte Activation / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D010957:Plasmids / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein
D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein