Roles for lipid heterogeneity in immunoreceptor signaling

Abstract

Immune receptors that specifically recognize foreign antigens to activate leukocytes in adaptive immune responses belong to a family of multichain cell surface proteins. All of these contain immunoreceptor tyrosine-based activation motifs in one or more subunits that initiate signaling cascades following stimulated tyrosine phosphorylation by Src-family kinases. As highlighted in this review, lipids participate in this initial activation step, as well as in more downstream signaling steps. We summarize evidence for cholesterol-dependent ordered lipids serving to regulate the store-operated Ca(2+) channel, Orai1, and we describe the sensitivity of Orai1 coupling to the ER Ca(2+) sensor, STIM1, to inhibition by polyunsaturated fatty acids. Phosphoinositides play key roles in regulating STIM1-Orai1 coupling, as well as in the stimulated Ca(2+) oscillations that are a consequence of IgE receptor signaling in mast cells. They also participate in the coupling between the plasma membrane and the actin cytoskeleton, which regulates immune receptor responses in T cells, B cells, and mast cells, both positively and negatively, depending on the cellular context. Recent studies show that other phospholipids with mostly saturated acylation also participate in coupling between receptors and the actin cytoskeleton. Lipid heterogeneity is a central feature of the intimate relationship between the plasma membrane and the actin cytoskeleton. The detailed nature of these interactions and how they are dynamically regulated to initiate and propagate receptor-mediated cell signaling are challenging questions for further investigation. This article is part of a Special Issue entitled: The cellular lipid landscape edited by Tim P. Levine and Anant K. Menon.

Keywords: Actin cytoskeleton; Calcium mobilization; Critical fluctuations; IgE receptors; Liquid ordered lipids; Phosphoinositides.

Figure 1

Schematic representation of the coalescence of clustered IgE receptors with Lyn kinase in ordered regions of the plasma membrane that are enriched in GPI-linked proteins, glycosphingolipids, phospholipids with saturated acyl chains, and cholesterol. Also shown is association of F-actin with these regions indicated by several studies, as discussed in Sec. 4. Figure is from (75).

Figure 2

Antigen crosslinks IgE/FcεRI complexes to initiate a tyrosine phosphorylation cascade that results in the activation of both PLCγ and Cdc42. Hydrolysis of PIP₂ by PLCγ produces IP₃, which mediates Ca²⁺ release from ER stores to stimulate SOCE that is necessary for degranulation. Activation of Cdc42 is important for sustained Ca²⁺ responses, including sustained Ca²⁺ oscillations, possibly because it promotes PIP5-kinase-mediated synthesis of PIP₂ via a mechanism that involves activation of protein kinase C. Modified from (23).

Figure 3

Activation of Ca²⁺ responses by streptavidin (SA) crosslinking of biotinylated huIgE bound to the chimeric IgE receptor αζζ expressed in RBL-2H3 mast cells is enhanced ~30–50% by cytochalasin D (cyto D) added after (A) or before (B) 3 nM SA. Ca²⁺ responses were monitored by steady-state fluorimetry at 37°C in a basal salt solution. Each addition of cyto D is 1 μM.

Figure 4

Activation of Ca²⁺ responses by multivalent DNP-BSA crosslinking of anti-DNP-IgE bound to the chimeric IgE receptor αζζ expressed in Jurkat T cells (A) is inhibited ~20% by pre-addition of 2 μM cyto D, which stimulates a small response itself in these cells (B).