VMP1 prevents Ca(2+) overload in endoplasmic reticulum and maintains naive T cell survival

Ca(2+) in endoplasmic reticulum (ER) dictates T cell activation, proliferation, and function via store-operated Ca(2+) entry. How naive T cells maintain an appropriate level of Ca(2+) in ER remains poorly understood. Here, we show that the ER transmembrane protein VMP1 is essential for maintaining ER Ca(2+) homeostasis in naive T cells. VMP1 promotes Ca(2+) release from ER under steady state, and its deficiency leads to ER Ca(2+) overload, ER stress, and secondary Ca(2+) 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 Ca(2+) 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 Ca(2+). These data uncover an indispensable role of VMP1 in preventing ER Ca(2+) overload and maintaining naive T cell survival.