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Diacylglycerol kinase ? establishes T cell polarity by shaping diacylglycerol accumulation at the immunological synapse.

ABSTRACT: Polarization of the T cell microtubule-organizing center (MTOC) to the immunological synapse between the T cell and an antigen-presenting cell (APC) maintains the specificity of T cell effector responses by enabling directional secretion toward the APC. The reorientation of the MTOC is guided by a sharp gradient of the second messenger diacylglycerol (DAG), which is centered at the immunological synapse. We used a single-cell photoactivation approach to demonstrate that diacylglycerol kinase ? (DGK-?), which catalyzes the conversion of DAG to phosphatidic acid, determined T cell polarity by limiting the diffusion of DAG. DGK-?-deficient T cells exhibited enlarged accumulations of DAG at the immunological synapse, as well as impaired reorientation of the MTOC. In contrast, T cells lacking the related isoform DGK-? did not display polarization defects. We also found that DGK-? localized preferentially to the periphery of the immunological synapse, suggesting that it constrained the area over which DAG accumulated. Phosphoinositide 3-kinase activity was required for the peripheral localization pattern of DGK-?, which suggests a link between DAG and phosphatidylinositol signaling during T cell activation. These results reveal a previously unappreciated function of DGK-? and provide insight into the mechanisms that determine lymphocyte polarity.

SUBMITTER: Chauveau A

PROVIDER: S-EPMC4993625 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Diacylglycerol kinase α establishes T cell polarity by shaping diacylglycerol accumulation at the immunological synapse.

Chauveau Anne A Le Floc'h Audrey A Bantilan Niels S NS Koretzky Gary A GA Huse Morgan M

Science signaling 20140826 340

Polarization of the T cell microtubule-organizing center (MTOC) to the immunological synapse between the T cell and an antigen-presenting cell (APC) maintains the specificity of T cell effector responses by enabling directional secretion toward the APC. The reorientation of the MTOC is guided by a sharp gradient of the second messenger diacylglycerol (DAG), which is centered at the immunological synapse. We used a single-cell photoactivation approach to demonstrate that diacylglycerol kinase α ( ...[more]

PMID: 25161317

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Project description:BACKGROUND:Polarity is necessary for epithelial cells to perform distinct functions at their apical and basal surfaces. Oral epithelial cell-derived ameloblasts at secretory stage (SABs) synthesize large amounts of enamel matrix proteins (EMPs), largely amelogenins. EMPs are unidirectionally secreted into the enamel space through their apical cytoplasmic protrusions, or Tomes' processes (TPs), to guide the enamel formation. Little is known about the transcriptional regulation underlying the establishment of cell polarity and unidirectional secretion of SABs. RESULTS:The higher-order chromatin architecture of eukaryotic genome plays important roles in cell- and stage-specific transcriptional programming. A genome organizer, special AT-rich sequence-binding protein 1 (SATB1), was discovered to be significantly upregulated in ameloblasts compared to oral epithelial cells using a whole-transcript microarray analysis. The Satb1-/- mice possessed deformed ameloblasts and a thin layer of hypomineralized and non-prismatic enamel. Remarkably, Satb1-/- ameloblasts at the secretory stage lost many morphological characteristics found at the apical surface of wild-type (wt) SABs, including the loss of Tomes' processes, defective inter-ameloblastic adhesion, and filamentous actin architecture. As expected, the secretory function of Satb1-/- SABs was compromised as amelogenins were largely retained in cells. We found the expression of epidermal growth factor receptor pathway substrate 8 (Eps8), a known regulator for actin filament assembly and small intestinal epithelial cytoplasmic protrusion formation, to be SATB1 dependent. In contrast to wt SABs, EPS8 could not be detected at the apical surface of Satb1-/- SABs. Eps8 expression was greatly reduced in small intestinal epithelial cells in Satb1-/- mice as well, displaying defective intestinal microvilli. CONCLUSIONS:Our data show that SATB1 is essential for establishing secretory ameloblast cell polarity and for EMP secretion. In line with the deformed apical architecture, amelogenin transport to the apical secretory front and secretion into enamel space were impeded in Satb1-/- SABs resulting in a massive cytoplasmic accumulation of amelogenins and a thin layer of hypomineralized enamel. Our studies strongly suggest that SATB1-dependent Eps8 expression plays a critical role in cytoplasmic protrusion formation in both SABs and in small intestines. This study demonstrates the role of SATB1 in the regulation of amelogenesis and the potential application of SATB1 in ameloblast/enamel regeneration.

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Diacylglycerol kinase ? establishes T cell polarity by shaping diacylglycerol accumulation at the immunological synapse.

Publications

Diacylglycerol kinase α establishes T cell polarity by shaping diacylglycerol accumulation at the immunological synapse.

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