Anoctamin8 Tethers the Endoplasmic Reticulum and Plasma Membranes to Assemble Ca 2+ Signaling Complexes at ER/PM Junctions

Communication and material transfer between membranes and organelles take place at membrane contact sites (MCSs). MCSs between the ER and PM, the ER/PM junctions, are the site where the ER Ca 2+ sensor STIM1 and the PM Ca 2+ influx channel Orai1 cluster. MCSs are formed by tether proteins that bridge the opposing membranes, but the identity and role of these tethers in receptor-evoked Ca 2+ signaling is not well understood. Here we identified ANO8 as a key tether in the formation of the ER/PM junctions that is essential for STIM1-STIM1 and STIM1-Orai1 interaction and channel activation at a PI(4,5)P 2 -rich domain. Moreover, ANO8 assembles all core Ca 2+ signaling proteins: Orai1, PMCA, STIM1, IP 3 receptors and SERCA2 at the ER/PM junctions. This controls the efficiency of receptor-stimulated Ca 2+ signaling and duration of Orai1 activity to prevent Ca 2+ toxicity. These findings reveal the central role of MCSs in determining efficiency and fidelity of cell signaling.

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