Ca2+ in endoplasmic reticulum (ER) dictates T cell activation, proliferation, and function via store-operated Ca2+ entry. How naive T cells maintain an appropriate level of Ca2+ in ER remains poorly understood. Here, we show that the ER transmembrane protein VMP1 is essential for maintaining ER Ca2+ homeostasis in naive T cells. VMP1 promotes Ca2+ release from ER under steady state, and its deficiency leads to ER Ca2+ overload, ER stress, and secondary Ca2+ overload in mitochondria, resulting in massive apoptosis of naive T cells and defective T cell response. Aspartic acid 272 (D272) of VMP1 is critical for its ER Ca2+ releasing activity, and a knockin mouse strain with D272 mutated to asparagine (D272N) demonstrates all functions of VMP1 in T cells in vivo depend on its regulation of ER Ca2+. These data uncover an indispensable role of VMP1 in preventing ER Ca2+ overload and maintaining naive T cell survival.
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