Diacylglycerol kinase ζ controls diacylglycerol metabolism at the immunological synapse

Gharbi, Severine; Rincón, Esther; Ávila-Flores, Antonia; Torres‐Ayuso, Pedro; Almena, María; Cobos, María Angeles; Albar, Juan Pablo; Mérida, Isabel

doi:10.1091/mbc.e11-03-0247

Cited by 45 publications

(75 citation statements)

References 39 publications

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“…4). The limited accumulation of DAG at the T cell-APC contact area requires DGKz activity and correlates with impaired expression of Il2 (41). In this model, consistent with previous findings (21), sustained membrane localization of GFP-DGKa was only observed for a kinase-deficient mutant.…”

Section: Isoform-specific Dgk Function In the Spatial Control Of Dag supporting

confidence: 90%

“…3). The predominant contribution of DGKz in suppressing the Ras-ERK pathway in primary T lymphocytes confirms findings from a study of the genetic silencing of these two isoforms in Jurkat cells (41). Although endogenous DGKa and DGKz both associate with the immunoprecipitated TCR-CD28 complex, knockdown of only the DGKz isoform impairs complex-associated DGK activity.…”

Section: Dgkz Is Functionally Coupled To Pkc and Rasgrp1 And Limits Tsupporting

confidence: 82%

“…2) (40). A mutant DGKz bearing serine-to-alanine mutations in this region did not relocate to the plasma membrane in Jurkat cells, did not consume DAG, and had no effect on expression of the gene encoding IL-2 (41). Phosphorylation of the DGKz MARCKS domain is thought to release the negative restriction imposed by the C-terminal domain, which has four ankyrinlike repeats and a PDZ-binding domain that interacts with PDZ-containing proteins (PDZbm) (42,43).…”

Section: Dgkz Is Functionally Coupled To Pkc and Rasgrp1 And Limits Tmentioning

confidence: 99%

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Redundant and specialized roles for diacylglycerol kinases α and ζ in the control of T cell functions

et al. 2015

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The diacylglycerol kinases (DGKs) attenuate diacylglycerol (DAG)-mediated signals by catalyzing the conversion of DAG to phosphatidic acid. In T lymphocytes, the antigen-stimulated generation of DAG links signal strength to the intensity and duration of signaling by the Ras-extracellular signal-regulated kinase (ERK) and protein kinase C (PKC)-dependent pathways. The generation of DAG at the plasma membrane of T cells lies at the core of the mechanisms that delimit T cell functions. DGKα and DGKζ are the two main isoforms that are found in T cells, and several approaches define their precise contribution to T cell responses. Each of these isoforms has specialized and redundant functions that limit the intensity of DAG-regulated signals downstream of antigenic stimulation. This ability, which in normal T cells contributes to maintaining homeostasis and function, is exploited by tumors to evade immune surveillance. Modification of DGK activity offers new perspectives for the therapeutic manipulation of T cell functions for treatment of autoimmune pathologies, or for overcoming tumor-induced T cell tolerance. Precise knowledge of the mechanisms that sustain DGK isoform-specific regulation in T lymphocytes is indispensable for the development of new tools for pharmacological intervention.

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Section: Isoform-specific Dgk Function In the Spatial Control Of Dag supporting

confidence: 90%

Section: Dgkz Is Functionally Coupled To Pkc and Rasgrp1 And Limits Tsupporting

confidence: 82%

Section: Dgkz Is Functionally Coupled To Pkc and Rasgrp1 And Limits Tmentioning

confidence: 99%

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Redundant and specialized roles for diacylglycerol kinases α and ζ in the control of T cell functions

et al. 2015

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“…Both DGKα and DGKζ suppress DAG-mediated signaling after TCR engagement (8, 9, 18), but a direct comparison of the role of DGKα and DGKζ in primary T cells has not yet been performed. We predicted that differences in the ability of DGKα and DGKζ to regulate TCR signaling might mirror the observed differences in their functions in vivo, such that DGKζ would exhibit greater control over DAG-mediated TCR signaling than would DGKα.…”

Section: Resultsmentioning

confidence: 99%

The ζ Isoform of Diacylglycerol Kinase Plays a Predominant Role in Regulatory T Cell Development and TCR-Mediated Ras Signaling

et al. 2013

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Diacylglycerol (DAG) is a critical second messenger that mediates T cell receptor (TCR)–stimulated signaling. The abundance of DAG is reduced by the diacylglycerol kinases (DGKs), which catalyze the conversion of DAG to phosphatidic acid (PA) and thus inhibit DAG-mediated signaling. In T cells, the predominant DGK isoforms are DGKα and DGKζ, and deletion of the genes encoding either isoform enhances DAG-mediated signaling. We found that DGKζ, but not DGKα, suppressed the development of natural regulatory T (Treg) cells and predominantly mediated Ras and Akt signaling downstream of the TCR. The differential functions of DGKα and DGKζ were not attributable to differences in protein abundance in T cells or in their localization to the contact sites between T cells and antigen-presenting cells. RasGRP1, a key DAG-mediated activator of Ras signaling, associated to a greater extent with DGKζ than with DGKα; however, in silico modeling of TCR-stimulated Ras activation suggested that a difference in RasGRP1 binding affinity was not sufficient to cause differences in the functions of each DGK isoform. Rather, the model suggested that a greater catalytic rate for DGKζ than for DGKα might lead to DGKζ exhibiting increased suppression of Ras-mediated signals compared to DGKα. Consistent with this notion, experimental studies demonstrated that DGKζ was more effective than DGKα at catalyzing the metabolism of DAG to PA after TCR stimulation. The enhanced effective enzymatic production of PA by DGKζ is therefore one possible mechanism underlying the dominant functions of DGKζ in modulating Treg cell development.

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“…Movement of the centrosome to the membrane at the edge of the cSMAC is a key step in IS-induced cell polarization, which has been observed in CTLs (Stinchcombe et al, 2006) as well as in CD4 cells (Ueda et al, 2011), NK and NKT cells (Stinchcombe et al, 2011), indicating that docking of the centrosome to the plasma membrane is a common event in direct secretion. The cytoskeleton and motor proteins such as dynein, as well as diacyl-glycerol (DAG) accumulation and restriction to the IS and other TCR signaling players, have been suggested to play a role in inducing the movement of the centrosome (Gharbi et al, 2011; Quann et al, 2009). Several candidate proteins have been suggested to also be involved at the centrosome polarization (reviewed in (Angus and Griffiths, 2013). )…”

Section: The Immunological Synapsementioning

confidence: 99%

“Cell Biology Meets Physiology

Curado¹,

Kumari²,

Dustin³

2013

Current Topics in Membranes

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The immunological synapse is an excellent example of cell-cell communication, where signals are exchanged between two cells, resulting in a well-structured line of defense during adaptive immune response. This process has been the focus of several studies that aimed at understanding its formation and subsequent events and has led to the understanding that it relies on a well-orchestrated molecular program that only occurs when specific requirements are met. The development of more precise and controllable T cell activation systems has led to new insights including the role of mechanotransduction in the process of formation of the immunological synapse and T cell activation. Continuous advances in our understanding of the immunological synapse formation, particularly in the context of T cell activation and differentiation, as well the development of new T cell activation systems are being applied to the establishment and improvement of immune therapeutical approaches.

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Diacylglycerol kinase ζ controls diacylglycerol metabolism at the immunological synapse

Cited by 45 publications

References 39 publications

Redundant and specialized roles for diacylglycerol kinases α and ζ in the control of T cell functions

Redundant and specialized roles for diacylglycerol kinases α and ζ in the control of T cell functions

The ζ Isoform of Diacylglycerol Kinase Plays a Predominant Role in Regulatory T Cell Development and TCR-Mediated Ras Signaling

“Cell Biology Meets Physiology

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