Anoctamin 8 tethers endoplasmic reticulum and plasma membrane for assembly of Ca ²⁺ signaling complexes at the ER/PM compartment

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 Ca2+ sensor STIM1 and the PM Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ influx into the ER. This controls the efficiency of receptor‐stimulated Ca2+ signaling, Ca2+ oscillations, and duration of Orai1 activity to prevent Ca2+ toxicity. These findings reveal the central role of MCSs in determining efficiency and fidelity of cell signaling.

Niclosamide repurposed for the treatment of inflammatory airway disease

“…TMEM16 proteins enhance GPCR-induced Ca 2+ signals by tethering the ER to the plasma membrane, by Ca 2+ influx through TMEM16F, and by refilling the ER Ca 2+ store (29,51). ER tethering has also been shown for TMEM16H (40). TMEM16 paralogs may also enhance Ca 2+ signals by increasing phosphatidylinositol 4,5-bisphosphate in the plasma membrane (52).…”

“…Unlike TMEM16F, TMEM16A does not transport phospholipids and operates as a Cl --selective ion channel (39). Yet, both paralogs support intracellular compartmentalized Ca 2+ signals (29), and a similar role has been found recently for TMEM16H (40). To further rule out additional effects of niclosamide, a double knockout of TMEM16A/F in mice would have been very useful.…”

Dysregulated calcium homeostasis prevents plasma membrane repair in Anoctamin 5/TMEM16E-deficient patient muscle cells

“…This implicates ANO5 in regulation of ER physiology. A TMEM16 protein family member Ist2 regulates ER morphology and ER-plasma membrane association in yeast 44 while another member - ANO8 facilitates this in mammalian cells 45 . ER-PM tethering is crucial for cellular calcium homeostasis in mammalian cells 46 .…”

Comparative transcriptomic analysis of deep- and shallow-water barnacle species (Cirripedia, Poecilasmatidae) provides insights into deep-sea adaptation of sessile crustaceans

“…Genes related to ion channel proteins were also positively selected, e.g., the anoctamin-8 and neurotransmitter-gated ion-channel transmembrane domain (Table 4). The former is a key tether protein that helps Ca 2+ across membrane transport and assembles all core Ca 2+ -signaling proteins at the endoplasmic reticulum and plasma membrane junctions [66]; the latter is a key domain of ion channels that allows ions, such as Na + , K + , Ca 2+ , and/or Cl − to pass through the membrane when binding a neurotransmitter [67]. Jointly, the expanded and positively selected of genes concerned with ligand binding and ion channel proteins would help G. gigas maintain signal transmission in the deep-sea environment.…”