Publication in detail

Proc Natl Acad Sci U S A. 2019 May 21;116(21):10392-10401. doi: 10.1073/pnas.1821399116. Epub 2019 May 7.

Remodeling of ER-plasma membrane contact sites but not STIM1 phosphorylation inhibits Ca2+ influx in mitosis.

Yu, F; Hubrack, SZ; Chakraborty, S; Sun, L; Alcantara-Adap, E; Kulkarni, R; Billing, AM; Graumann, J; Taylor, CW; Machaca, K

Department of Physiology and Biophysics & Calcium Signaling Group & Department of Biochemistry, Weill Cornell Medicine Qatar, Doha, Qatar, 24144. Department of Pharmacology, University of Cambridge, CB2 1PD Cambridge, United Kingdom.

Store-operated Ca2+ entry (SOCE), mediated by the endoplasmic reticulum (ER) Ca2+ sensor stromal interaction molecule 1 (STIM1) and the plasma membrane (PM) channel Orai1, is inhibited during mitosis. STIM1 phosphorylation has been suggested to mediate this inhibition, but it is unclear whether additional pathways are involved. Here, we demonstrate using various approaches, including a nonphosphorylatable STIM1 knock-in mouse, that STIM1 phosphorylation is not required for SOCE inhibition in mitosis. Rather, multiple pathways converge to inhibit Ca2+ influx in mitosis. STIM1 interacts with the cochaperone BAG3 and localizes to autophagosomes in mitosis, and STIM1 protein levels are reduced. The density of ER-PM contact sites (CSs) is also dramatically reduced in mitosis, thus physically preventing STIM1 and Orai1 from interacting to activate SOCE. Our findings provide insights into ER-PM CS remodeling during mitosis and a mechanistic explanation of the inhibition of Ca2+ influx that is required for cell cycle progression.

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