Anoctamin 8 tethers endoplasmic reticulum and plasma membrane for assembly of Ca2+ signaling complexes at the ER/PM compartment. (6th May 2019)

• Record Type: Journal Article
• Authors: Jha, Archana; Chung, Woo Young; Vachel, Laura; Maleth, Jozsef; Lake, Sarah; Zhang, Guofeng; Ahuja, Malini; Muallem, Shmuel
• Is Part Of: EMBO journal. Volume 38:Number 12(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-05-06
• Subjects: ANO8 -- assembly -- Ca2+ -- signaling -- tether; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2018101452
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: 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 sites 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 Anoctamin 8 (ANO8) as a key tether in the formation of the ER/PM junctions that is essential for STIM1‐STIM1 interaction and STIM1‐Orai1 interaction and channel activation at a ER/PM PI(4, 5)P2 ‐rich compartment. Moreover, ANO8 assembles all core Ca 2+ signaling proteins: Orai1, PMCA, STIM1, IP3 receptors, and SERCA2 at the ER/PM junctions to mediate a novel form of Orai1 channel inactivation by markedly facilitating SERCA2‐mediated Ca 2+ influx into the ER. This controls the efficiency of receptor‐stimulated Ca 2+ signaling, Ca 2+ oscillations, 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. Synopsis: ER and plasma membrane (PM) form tight membrane intersections, where Ca 2+ sensor STIM1 and influx channel Orai1 cluster to confer receptor‐stimulated signaling. A new screen identifies Anoctamin 8 (ANO8), a mammalian chloride channel family member, as key tether for ER/PM junctions, regulating STIM1‐Orai1 interactions and determining duration of Orai1‐dependent Ca 2+ oscillations. ANO8 associates with STIM1 and Oria1 and controls their interaction. ANO8 increases STIM1‐Orai1 clusters at ER/PM junctions. ANO8 mediates slow, SARAF‐independent Orai1 inactivation at very low cytoplasmic calcium concentrations. ANO8 function depends on interaction with PM lipid PI(4, 5)P2. ANO8 assembles all core calcium‐signaling factors at the PI(4, 5)P2‐rich compartment. Abstract : Anoctamin 8 exerts channel‐independent roles in ER/PM junction formation and receptor‐stimulated Ca 2+ oscillations.