SLAT-IP3R interaction: implications and functional relevance in T cell activation and calcium signaling (P1172)

Abstract SWAP-70-like adaptor of T cells (SLAT) is a guanine nucleotide exchange factor for Rho GTPases that regulates the activation and differentiation of CD4+ T cells by controlling the Ca2+-NFAT signaling pathway. In response to T cell receptor (TCR)/CD28 costimulation, SLAT promotes calcium signaling by regulating calcium release from endoplasmic reticulum (ER) stores. Hence, SLAT-deficient T cells display a severe defect in Ca2+ release from the ER, despite normal activation of PLCg1 and intact production of inositol-1,4,5-trisphosphate (IP3). Here we report a direct and TCR-induced association between SLAT and the (IP3) receptor type 1 (IP3R1), an ER-resident calcium channel, which mediates calcium release from intracellular stores. Using biochemical approaches, we found that both a N-terminal domain, containing an EF-hand motif, and the pleckstrin homology (PH) domain of SLAT bind directly a defined ~20 amino acid region in the regulatory domain of IP3R1. Subcellular fractionation analysis showed that SLAT is present in the ER compartment. Altogether, these data prompt us to hypothesize that SLAT is required for proper IP3R function in T cells, reflecting its direct interaction with the IP3R. Current studies, including strategies aimed at blocking and disrupting the SLAT-IP3R1 interaction, are aimed at determining the biological significance of this novel interaction and its importance for the overall TCR/CD28-induced Ca2+ signaling pathway in T lymphocytes.