Selective Accumulation of Raft-Associated Membrane Protein Lat in T Cell Receptor Signaling Assemblies

Harder, Thomas; Kuhn, Marina

doi:10.1083/jcb.151.2.199

Cited by 140 publications

(146 citation statements)

References 54 publications

Supporting

Mentioning

130

Contrasting

Order By: Relevance

“…First, LAT was not recruited to TCR-enriched immunoisolates in cells treated with the potent Src kinase inhibitor PP2 (Harder and Kuhn 2000). Second, imaging approaches using planar substrates demonstrated that LAT variants with mutated tyrosines in the cytoplasmic tail were not recruited to signaling microclusters (Douglass and Vale 2005;Bunnell et al 2006;Houtman et al 2006).…”

Section: Mechanisms Of Assembly Of Lat Clusters and Lat-nucleated Commentioning

confidence: 99%

The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

Balagopalan¹,

Coussens²,

Sherman³

et al. 2010

Cold Spring Harbor Perspectives in Biology

152

184

View full text Add to dashboard Cite

The adapter molecule LAT is a nucleating site for multiprotein signaling complexes that are vital for the function and differentiation of T cells. Extensive investigation of LAT in multiple experimental systems has led to an integrated understanding of the formation, composition, regulation, dynamic movement, and function of LAT-nucleated signaling complexes. This review discusses interactions of signaling molecules that bind directly or indirectly to LAT and the role of cooperativity in stabilizing LAT-nucleated signaling complexes. In addition, it focuses on how imaging studies visualize signaling assemblies as signaling clusters and demonstrate their dynamic nature and cellular fate. Finally, this review explores the function of LAT based on the interpretation of mouse models using various LAT mutants.

show abstract

Section: Mechanisms Of Assembly Of Lat Clusters and Lat-nucleated Commentioning

confidence: 99%

The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

Balagopalan¹,

Coussens²,

Sherman³

et al. 2010

Cold Spring Harbor Perspectives in Biology

152

184

View full text Add to dashboard Cite

show abstract

“…As with GPI-GFP, when EqtII-Atto655 was added to cells transfected with common raft markers like Myr-Pal-YFP or LAT-GFP (24,25,41,42), a profound reorganization of the fluorescent proteins was observed in the course of a few minutes ( Fig. 3 and supplemental Movies S3-S5).…”

Section: Equinatoxin II Clustering Reorganizes the Plasma Membrane Anmentioning

confidence: 99%

Oligomerization and Pore Formation by Equinatoxin II Inhibit Endocytosis and Lead to Plasma Membrane Reorganization

García‐Sáez

Buschhorn

Keller

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Pore-forming toxins have evolved to induce membrane injury by formation of pores in the target cell that alter ion homeostasis and lead to cell death. Many pore-forming toxins use cholesterol, sphingolipids, or other raft components as receptors. However, the role of plasma membrane organization for toxin action is not well understood. In this study, we have investigated cellular dynamics during the attack of equinatoxin II, a poreforming toxin from the sea anemone Actinia equina, by combining time lapse three-dimensional live cell imaging, fluorescence recovery after photobleaching, FRET, and fluorescence crosscorrelation spectroscopy. Our results show that membrane binding by equinatoxin II is accompanied by extensive plasma membrane reorganization into microscopic domains that resemble coalesced lipid rafts. Pore formation by the toxin induces Ca 2؉ entry into the cytosol, which is accompanied by hydrolysis of phosphatidylinositol 4,5-bisphosphate, plasma membrane blebbing, actin cytoskeleton reorganization, and inhibition of endocytosis. We propose that plasma membrane reorganization into stabilized raft domains is part of the killing strategy of equinatoxin II.Pore-forming proteins (PFPs) 4 have been developed by many organisms ranging from bacteria and parasites to animals to disrupt membrane integrity of the target cell. The purpose of membrane permeabilization in many cases is to compromise cell survival, as it happens with toxins like ␣-toxin, actinoporins, or the proteins of the Bcl-2 family and perforin in human cells. However, it can also be related with the escape of certain bacteria from the phagosome, like listeriolysin, or with protein delivery into the cytosol, as in the case of colicins (1-3).PFPs are secreted by the producer cell in soluble form and bind to target cells via specific receptors. Then they undergo a conformational change that exposes hydrophobic residues and allows their insertion into the plasma membrane and oligomerization into a pore. The nature, stoichiometry, and size of that pore depend on the PFP (1). In vitro studies suggest that the toxins of the actinoporin family form a tetramer (4 -6), although it could also have a structure similar to those recently reported for cytolysin A or fragaceatoxin C (7, 8), with a higher oligomeric state. The nature of the pore is believed to be toroidal, with lipids exposed to the pore lumen (9). In red blood cells and on artificial lipid vesicles, actinoporins formed pores ϳ2 nm in diameter (10, 11).Many PFPs use molecules associated with lipid rafts as receptors (12). Rafts are lipid/protein domains enriched in cholesterol and sphingolipids that act as signaling platforms in the plasma membrane of the cell. During the last years, there has been extensive debate over what rafts are and their functional role. Different domains of raft nature have been observed in several temporal and spatial scales. As a consequence, there are many different kinds of domains that have been associated with rafts (13).Some examples of raft-associated toxin...

show abstract

“…LAT was recently shown (31,39,40) to depend on raft localization to function in T cell signaling. Moreover, LAT seems to be specifically located in the vicinity of the TCR, and this vicinity is lost by preventing the raft localization of LAT (41). When displaced from membrane rafts, LAT phosphorylation is either blocked as in PUFAtreated PBTLs or parental Jurkat T cells (Fig.…”

Section: Pag-lat Chimeric Protein Is Retained In Rafts Of Pufaenrichementioning

confidence: 99%

LAT Displacement from Lipid Rafts as a Molecular Mechanism for the Inhibition of T Cell Signaling by Polyunsaturated Fatty Acids

Zeyda¹,

Staffler²,

Hořejšı́³

et al. 2002

Journal of Biological Chemistry

152

105

View full text Add to dashboard Cite

Polyunsaturated fatty acids (PUFAs) suppress immune responses and inhibit T cell activation through largely unknown mechanisms. The displacement of signaling proteins from membrane lipid rafts has recently been suggested as underlying PUFA-mediated T cell inhibition. We show here that PUFA treatment specifically interferes with T cell signal transduction by blocking tyrosine phosphorylation of LAT (linker for activation of T cells) and phospholipase C␥1. A significant fraction of LAT was displaced from rafts by PUFA treatment along with other signaling proteins. However, retaining LAT alone in lipid rafts effectively restored phospholipase C␥1/calcium signaling in PUFA-treated T cells. These data reveal LAT displacement from lipid rafts as a molecular mechanism by which PUFAs inhibit T cell signaling and underline the predominant importance of LAT localization in rafts for efficient T cell activation. Polyunsaturated fatty acids (PUFAs)1 suppress immune responses (1) and are clinically applied as adjuvant immunosuppressive agents in the treatment of inflammatory disorders (e.g. rheumatoid arthritis and inflammatory bowel disease) (2, 3) and following organ transplantation (4). PUFAs of the n-3 series have been shown to be particularly effective and are known to interfere with proinflammatory eicosanoid (prostaglandin/leukotriene) synthesis (1). However, PUFA-mediated inhibition of T lymphocyte activation and function has repeatedly been shown to be independent of eicosanoid synthesis (5-8). The molecular mechanism by which PUFAs inhibit T cell signal transduction has remained largely unknown. Because PUFA treatment changes the lipid composition of lymphocyte membranes (9) and functionally important membrane lipid rafts (10), alterations of rafts have been suggested as underlying the PUFA-mediated inhibition of T cell signaling (11).Membrane lipid rafts or microdomains are specialized regions within the plane of the plasma membrane and have been proposed as playing an essential role in T cell signal transduction (12-16). Lipid rafts are characterized by a high concentration of cholesterol and sphingolipids such as sphingomyelin and glycolipids, and their polar lipids contain predominantly saturated fatty acyl residues (17, 18). Such lipids spontaneously form liquid-ordered membrane regions that are insoluble in non-ionic detergents, facilitating raft isolation as detergentresistant membrane domains (18,19). Cytoplasmic and transmembrane proteins are targeted to lipid rafts mostly by acylation with saturated fatty acyl moieties (palmitoyl and myristoyl) which link these proteins to the cytoplasmic lipid leaflet of microdomains (20). Several proteins involved in T cell signaling such as Src family protein-tyrosine kinases (PTKs) and LAT (linker for activation of T cells) are concentrated in rafts because of post-translational palmitoylation, emphasizing the role of lipid rafts in T cell signaling (14, 21).The activation of T cells requires stimulation of the T cell antigen receptor (TCR)/CD3 complex. Triggering CD3...

show abstract

Selective Accumulation of Raft-Associated Membrane Protein Lat in T Cell Receptor Signaling Assemblies

Cited by 140 publications

References 54 publications

The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

Oligomerization and Pore Formation by Equinatoxin II Inhibit Endocytosis and Lead to Plasma Membrane Reorganization

LAT Displacement from Lipid Rafts as a Molecular Mechanism for the Inhibition of T Cell Signaling by Polyunsaturated Fatty Acids

Contact Info

Product

Resources

About