PIP5 Kinases Regulate Membrane Phosphoinositide and Actin Composition for Targeted Granule Secretion by Cytotoxic Lymphocytes.
Frazer, Gordon L
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Gawden-Bone, C., Frazer, G. L., Richard, A., Ma, C., Strege, K., & Griffiths, G. (2018). PIP5 Kinases Regulate Membrane Phosphoinositide and Actin Composition for Targeted Granule Secretion by Cytotoxic Lymphocytes.. Immunity, 49 (3), 427-437.e4. https://doi.org/10.1016/j.immuni.2018.08.017
How cytotoxic T lymphocytes (CTLs) sense T cell receptor (TCR) signaling in order to specialize an area of plasma membrane for granule secretion is not understood. Here, we demonstrate that immune synapse formation led to rapid localized changes in the phosphoinositide composition of the plasma membrane, both reducing phosphoinositide-4-phosphate (PI(4)P), PI(4,5)P2, and PI(3,4,5)P3 and increasing diacylglycerol (DAG) and PI(3,4)P2 within the first 2 min of synapse formation. These changes reduced negative charge across the synapse, triggering the release of electrostatically bound PIP5 kinases that are required to replenish PI(4,5)P2. As PI(4,5)P2 decreased, actin was depleted from the membrane, allowing secretion. Forced localization of PIP5Kβ across the synapse prevented actin depletion, blocking both centrosome docking and secretion. Thus, PIP5Ks act as molecular sensors of TCR activation, controlling actin recruitment across the synapse, ensuring exquisite co-ordination between TCR signaling and CTL secretion.
T-Lymphocytes, Cytotoxic, Cell Line, Cell Membrane, Cytoplasmic Granules, Animals, Mice, Inbred C57BL, Mice, Transgenic, Mice, Actins, Phosphotransferases (Alcohol Group Acceptor), Phosphatidylinositols, Receptors, Antigen, T-Cell, Lymphocyte Activation, Signal Transduction, Cell Degranulation, Cytotoxicity, Immunologic, Immunological Synapses
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (103930/Z/14/Z)
Medical Research Council (MR/P014178/1)
Addenbrooke's Charitable Trust (ACT) (Minute 23/17 A (ii))
Wellcome Trust (075880/Z/04/A)
External DOI: https://doi.org/10.1016/j.immuni.2018.08.017
This record's URL: https://www.repository.cam.ac.uk/handle/1810/283104
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/