Extended-Synaptotagmin-1 and -2 control T cell signaling and function

Upon T-cell activation, the levels of the secondary messenger diacylglycerol (DAG) at the plasma membrane need to be controlled to ensure appropriate T-cell receptor signaling and T-cell functions. Extended-Synaptotagmins (E-Syts) are a family of inter-organelle lipid transport proteins that bridge the endoplasmic reticulum and the plasma membrane. In this study, we identify a novel regulatory mechanism of DAG-mediated signaling for T-cell effector functions based on E-Syt proteins. We demonstrate that E-Syts downmodulate T-cell receptor signaling, T-cell-mediated cytotoxicity, degranulation, and cytokine production by reducing plasma membrane levels of DAG. Mechanistically, E-Syt2 predominantly modulates DAG levels at the plasma membrane in resting-state T cells, while E-Syt1 and E-Syt2 negatively control T-cell receptor signaling upon stimulation. These results reveal a previously underappreciated role of E-Syts in regulating DAG dynamics in T-cell signaling. Synopsis Extended-Synaptotagmin1 and -2 (E-Syt1 and -2) are lipid transport proteins at ER-plasma membrane contact sites and are responsible for downmodulating DAG levels at the plasma membrane, T cell receptor signaling, and T cell effector functions. E-Syt proteins regulate T cell receptor signaling and T cell functions through downmodulating DAG levels at the plasma membrane. E-Syt2 predominantly modulates plasma membrane DAG levels in resting state T cells. E-Syt1 and E-Syt2 redistribute into DAG-rich regions upon T cell activation. Extended-Synaptotagmin1 and -2 are lipid transport proteins at ER-plasma membrane contact sites and are responsible for downmodulating DAG levels at the plasma membrane, T cell receptor signaling, and T cell effector functions.