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

作者：Fos Camille; Becart Stephane; Balancio Ann J Canonigo; Boehning Darren; Altman Amnon^*

来源：Science Signaling, 2014, 7(345): ra93.

DOI：10.1126/scisignal.2005565

The guanine nucleotide exchange factor SLAT (SWAP-70-like adaptor of T cells) regulates T cell activation and differentiation by enabling Ca2+ 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 (IP(3)R1). The N-terminal region of SLAT, which contains two EF-hand motifs that we determined bound Ca2+, and the SLAT pleckstrin homology (PH) domain independently bound to IP(3)R1 by associating with a conserved motif within the IP(3)R1 ligand-binding domain. Disruption of the SLAT-IP(3)R1 interaction with cell-permeable, IP(3)R1-based fusion peptides inhibited TCR-stimulated Ca2+ 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 IP(3)R1-interacting protein required for T cell activation suggests that this interaction could be a potential target for a selective immunosuppressive drug.

• 出版日期2014-9-30