PIP5 Kinases Regulate Membrane Phosphoinositide and Actin Composition for Targeted Granule Secretion by Cytotoxic Lymphocytes.

Immunity
C Gawden-BoneGillian M Griffiths

Abstract

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.

Citations

Jan 30, 2019·The Journal of Biological Chemistry·William F Hawse, Richard T Cattley
Aug 1, 2019·Cells·Chiara Cassioli, Cosima T Baldari
Jul 25, 2019·Frontiers in Cell and Developmental Biology·Anna Onnis, Cosima T Baldari
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Feb 12, 2020·Proceedings of the National Academy of Sciences of the United States of America·Fella TamzalitMorgan Huse
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Methods Mentioned

BETA
pLAT
FRET
PCR
biosensor

Key Resources (RRID) Mentioned

CVCL_0255
IMSR_JAX

Software Mentioned

En
FlowJo
IncuCyte S3
mApple
ImageJ
Imaris
Lifeact
Prism
Face Lifeact

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