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SAP-Mediated Inhibition of Diacylglycerol Kinase alpha Regulates TCR-Induced Diacylglycerol Signaling

Baldanzi, Gianluca and Rainero, Elena and Filigheddu, Nicoletta and Mesturini, Riccardo and Song, Shuping and Patrussi, Laura and Zhong, Xiao-Ping and van Blitterswijk, Wim J. and Sinigaglia, Fabiola and Nichols, Kim E. and Rubio, Ignacio and Pighini, Andrea and Schweighoffer, Tamas and Parolini, Ornella and Graziani, Andrea and Bettio, Valentina and Traini, Sara and Chianale, Federica and Porporato, Paolo E. (2011) SAP-Mediated Inhibition of Diacylglycerol Kinase alpha Regulates TCR-Induced Diacylglycerol Signaling. Journal of Immunology, 187 (11). pp. 5941-5951. ISSN 0022-1767

Abstract

Diacylglycerol kinases (DGKs) metabolize diacylglcyerol to phosphatidic acid. In T lymphocytes, DGKα acts as a negative regulator of T cell receptor (TCR) signalling by decreasing
diacylglcyerol levels and inducing anergy. Here, we show that upon co-stimulation of the TCR with CD28 or SLAM, DGKα undergoes rapid negative regulation of its enzymatic activity and is recruited to the plasma membrane. Surprisingly, inhibition of DGKα is dependent on the expression of SAP, an adaptor protein mutated in X-linked lymphoproliferative disease (XLP). SAP, which is essential for SLAM-mediated signalling, also contributes to TCR/CD28-induced signalling and T cell activation. We observe that SAP silencing uncouples DGKα inhibition from its membrane recruitment, indicating that the two events are independently regulated. Furthermore in SAPdeficient cells inhibition of DGKα partially rescues defective TCR/CD28 signalling, including
activation of Ras and ERK-1/2, membrane recruitment of PKCθ, induction of NFAT transcriptional activity and IL-2 production. While SAP overexpression is sufficient to inhibit DGKα, Phospholipase C activity and calcium increase, but not Src-family tyrosine kinases, are also required for negative regulation of DGKα. These findings indicate that SAP-mediated inhibition of DGKα sustains diacylglycerol signalling, thereby regulating T cell activation and may suggest a
novel pharmacological strategy for XLP treatment.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2406

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