Mechanisms and regulation of Ca²⁺ leakage from the ER

We identified Sec61 complexes as major Ca²⁺ leak channels of the mammalian endoplasmic reticulum (ER). While the Ca²⁺leak is regulated by allosteric effectors such as BiP or TRAP, a point mutation in the Sec61 complex can cause a dysregulated Ca²⁺ flux, which we characterized as the root of primary antibody deficiency in humans. Recently, we decoded the signaling function of the Sec61-mediated Ca²⁺ leak. In our view, it serves as the signal of an ATP- Ca²⁺ cycle that replenishes the ATP demand of the ER via SLC35B1.

Next, we will study novel disease-associated Sec61 mutants, identify pharmacological modulators of the Sec61-mediated Ca²⁺ flux, characterize its regulation in sub-domains of the ER and determine its contribution to ER energy homeostasis.