Lipid signaling in T-cell development and function

Abstract

Second messenger molecules relay, amplify, and diversify cell surface receptor signals. Two important examples are phosphorylated D-myo-inositol derivatives, such as phosphoinositide lipids within cellular membranes, and soluble inositol phosphates. Here, we review how phosphoinositide metabolism generates multiple second messengers with important roles in T-cell development and function. They include soluble inositol(1,4,5)trisphosphate, long known for its Ca(2+)-mobilizing function, and phosphatidylinositol(3,4,5)trisphosphate, whose generation by phosphoinositide 3-kinase and turnover by the phosphatases PTEN and SHIP control a key "hub" of TCR signaling. More recent studies unveiled important second messenger functions for diacylglycerol, phosphatidic acid, and soluble inositol(1,3,4,5)tetrakisphosphate (IP(4)) in immune cells. Inositol(1,3,4,5)tetrakisphosphate acts as a soluble phosphatidylinositol(3,4,5)trisphosphate analog to control protein membrane recruitment. We propose that phosphoinositide lipids and soluble inositol phosphates (IPs) can act as complementary partners whose interplay could have broadly important roles in cellular signaling.

Figure 1.

The phosphoinositide PI(4,5)P₂ is a key node of second messenger metabolism in lymphocytes. PI(4,5)P₂-phosphorylation by PI3-kinases and PI(4,5)P₂-hydrolysis by PLCγ initiate several second messenger cascades within cellular membranes and soluble compartments. These second messengers can have various functions, including the recruitment and/or activation of effector proteins by binding to specific domains within them (blue arrows and green boxes). In particular, the phosphatases SHIP1/2 or PTEN limit or down-regulate PIP₃ levels and the functions of PIP₃ and its effectors by hydrolyzing PIP₃ into PI(3,4)P₂ or PI(4,5)P₂, respectively. For group 1D, PH domains such as that of Akt, PI(3,4)P₂ binding sustains effector activity (Cozier et al. 2004; DiNitto and Lambright 2006; Lemmon 2008). PI(4,5)P₂ recruits proteins such as RASA3/GAP1^IP4BP by binding to their PH domains (Lockyer et al. 1997; Cozier et al. 2000a; Cozier et al. 2000b). Hence, both PIP₂s and PIP₃ can have partially overlapping functions depending on the lipid-binding protein domain involved. PLCγ hydrolyzes PI(4,5)P₂ into protein C1 domain binding DAG and into IP₃, which binds EF and C2 domain containing proteins and mobilizes Ca²⁺. IP₃ 3-kinases convert IP₃ into IP₄, which acts as a soluble PIP₃ analog and controls the abilities of certain PH domains to bind to PIP₃ either positively (green arrow) or negatively (red arrow). An unknown 5-phosphatase metabolizes IP₄ into I(1,3,4)P₃, a precursor for higher-order IPs. In vitro, SHIP1 and PTEN can dephosphorylate IP₄ at the 5- or 3-positions, respectively (Erneux et al. 1998; Maehama and Dixon 1998; Pesesse et al. 1998; Caffrey et al. 2001). Whether this occurs physiologically is unknown. Finally, DAG kinases (DGKs) down-regulate DAG function by phosphorylating it into PA, itself a ligand for certain proteins. Further metabolism of all these second messengers results in the generation of many lipid and soluble metabolites. Several of these have important signaling functions (Irvine 2001; Irvine and Schell 2001; York and Hunter 2004; York 2006; Alcazar-Roman and Wente 2008; Huang et al. 2008; Jia et al. 2008b; Miller et al. 2008; Burton et al. 2009; Shears 2009; Sauer and Cooke 2010; Schell 2010). Their functions in immunocytes are unknown.

Figure 2.

Schematic structures of key PIP₂ or IP₃ kinases and PIP₂ lipases in lymphocytes. For details, see text.

Figure 3.

Schematic structures of key PIP₃ or IP₄ phosphatases and DAG kinases in lymphocytes. For details, see text.