title: Association of the EF-hand and PH domains of the guanine nucleotide exchange factor SLAT with IP₃ receptor 1 promotes Ca²⁺ signaling in T cells.
abstract: The guanine nucleotide exchange factor SLAT (SWAP-70-like adaptor of T cells) regulates T cell activation and differentiation by enabling Ca(2+) release from intracellular stores in response to stimulation of the T cell receptor (TCR). We found a TCR-induced association between SLAT and inositol 1,4,5-trisphosphate (IP3) receptor type 1 (IP3R1). The N-terminal region of SLAT, which contains two EF-hand motifs that we determined bound Ca(2+), and the SLAT pleckstrin homology (PH) domain independently bound to IP3R1 by associating with a conserved motif within the IP3R1 ligand-binding domain. Disruption of the SLAT-IP3R1 interaction with cell-permeable, IP3R1-based fusion peptides inhibited TCR-stimulated Ca(2+) signaling, activation of the transcription factor NFAT (nuclear factor of activated T cells), and production of cytokines, suggesting that this interaction is required for optimal T cell activation. The finding that SLAT is an IP3R1-interacting protein required for T cell activation suggests that this interaction could be a potential target for a selective immunosuppressive drug.
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Camille
authors.initials: C
authors.lastname: Fos
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Stephane
authors.initials: S
authors.lastname: Becart
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Ann J
authors.initials: AJ
authors.lastname: Canonigo Balancio
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Darren
authors.initials: D
authors.lastname: Boehning
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. amnon@liai.org.
authors.forename: Amnon
authors.initials: A
authors.lastname: Altman
mesh_terms: D000818:Animals; D015153:Blotting, Western; D020013:Calcium Signaling / Q000276:immunology*; D002458:Cell Fractionation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005822:Genetic Vectors / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors; D047468:Immunoprecipitation; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008156:Luciferases; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007371:Interferon-gamma; D008156:Luciferases; D009687:Nuclear Proteins; C473249:Def6 protein, mouse