The ER/PM junctions tether ANO8 regulates Orai1-STIM1 function by recruiting ORP8 to the junctions to determine PI(4)P and PI(4,5)P2 Levels

Authors

• A Movahed Abtahi
• B LeBlanc
• W Chung
• S Muallem

Abstract

Anoctamin-8 (ANO8) is a tether at the ER/PM junctions that facilitates recruitment and interaction of the ER Ca2+ sensor STIM1 and the pore-forming Orai1 to control Ca2+ influx in all cells. The mechanism by which ANO8 achieves this function has yet to be discovered. The phosphoinositide lipids PI(4)P and PI(4,5)P2 are enriched at the ER/PM junctions and are required for STIM1-Orai1 interaction and Ca2+ influx. Measurement of the lipids with biosensors revealed that ANO8 markedly increased the junctional levels of both PI(4)P and PI(4,5)P2. In a previous study, we reported that the lipid transfer protein Oxysterol-binding protein (OSBP)-related proteins (ORPs) ORP8 increase the level of PI(4)P at the ER-PM junctions. ANO8 specifically recruited the ORP8 to the junction to control the PI(4)P and PI(4,5)P2 levels. Interestingly, ANO8/ORP8 also increased the dynamic metabolism and turnover of the phosphoinositide lipids at the junctions, as revealed by alteration in their synthesis rate blocking by Li+ and by blocking of PLCβ. The changes in phosphoinositide lipids metabolism were faithfully translated to changes in Orai1-STIM1 mediated Ca2+ current. Ongoing studies continue to examine the role of ANO8 in phosphoinositide lipids metabolism as it relates to the regulation of cellular Ca2+ signaling.

Scientific Focus Area: Molecular Biology and Biochemistry

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