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bioRxiv · 10.1101/2023.12.25.573330

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

ying, M. y.·yi, W.·cui, Z. x.·gang, J.·jing, X.·yang, L. z.·na, Y.·bing, G. z.·qing, X. b.·min, P.
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Abstract

Naive T cells are metabolically quiescent. Here, we report an unexpected role of endoplasmic reticulum (ER) Ca2+ in preserving T cell metabolic quiescence. TMEM41B, an ER-resident membrane protein previously known for its crucial roles in autophagy, lipid scrabbling and viral infections, is identified as a novel type of concentration-dependent ER Ca2+ release channel. Ablation of TMEM41B induces ER Ca2+ overload, triggering the upregulation of IL-2 and IL-7 receptors in naive T cells. Consequently, this leads to increased basal signaling of the JAK-STAT, AKT-mTOR, and MAPK pathways, propelling TMEM41B-deficient naive T cells into a metabolically activated yet immunologically naive state. ER Ca2+ overload also downregulates CD5, a suppressor of TCR signaling, thereby reducing the activation threshold of TMEM41B-deficient T cells, resulting in attenuated tolerance and heightened T cell responses during infections. In summary, TMEM41B-mediated ER Ca2+ release is a pivotal determinant governing metabolic quiescence and responsiveness of naive T cells.

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ying, M. y., yi, W., cui, Z. x., gang, J., jing, X., yang, L. z., na, Y., bing, G. z., qing, X. b., min, P.. 2023-12-26. TMEM41B is an endoplasmic reticulum Ca2+ release channel maintaining T cell metabolic quiescence and responsiveness. https://doi.org/10.1101/2023.12.25.573330

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