TMEM41B is an endoplasmic reticulum Ca2+ release channel maintaining naive T cell quiescence and responsiveness

作者：Yuying Ma, Yi Wang, Xiaocui Zhao, Gang Jin, Jing Xu, Zhuoyang Li, Na Yin, Zhaobing Gao, Bingqing Xia, Min Peng · 发表于：Cell Discovery · 年份：2025 · DOI：10.1038/s41421-024-00766-w · 被引用次数：7 · 研究领域：Calcium signaling and nucleotide metabolism、Ion Channels and Receptors、Adenosine and Purinergic Signaling

Abstract In mammalian cells, endoplasmic reticulum (ER) passively releases Ca 2+ under steady state, but channels involved remain elusive. Here, we report that TMEM41B, an ER-resident membrane protein critical for autophagy, lipid metabolism, and viral infection, functions as an ER Ca 2+ release channel. Biochemically, purified recombinant TMEM41B forms a concentration-dependent Ca 2+ channel in single-channel electrophysiology assays. Cellularly, TMEM41B deficiency causes ER Ca 2+ overload, while overexpression of TMEM41B depletes ER Ca 2+ . Immunologically, ER Ca 2+ overload leads to upregulation of IL-2 and IL-7 receptors in naive T cells, which in turn increases basal signaling of JAK-STAT, AKT-mTOR, and MAPK pathways. This dysregulation drives TMEM41B-deficient naive T cells into a metabolically activated yet immunologically naive state. ER Ca 2+ overload also downregulates CD5, lowering the activation threshold of TMEM41B-deficient T cells and leading to heightened T cell responses during infections. In summary, we identify TMEM41B as a concentration-dependent ER Ca 2+ release channel, revealing an unexpected role of ER Ca 2+ in naive T cell quiescence and responsiveness.