Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 10, Pages 2762-2767Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1524229113
Keywords
junctophilins; ER-PM junctions; store-operated Ca2+ entry; STIM1; Orai1
Categories
Funding
- National Institutes of Health Grant [AI-083432]
- American Heart Association Grant [12SDG12040188]
- Japan Society for the Promotion of Sciences Core-to-Core Grant
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Orai1 and stromal interaction molecule 1 (STIM1) mediate store-operated Ca2+ entry (SOCE) in immune cells. STIM1, an endoplasmic reticulum (ER) Ca2+ sensor, detects store depletion and interacts with plasma membrane (PM)-resident Orai1 channels at the ER-PM junctions. However, the molecular composition of these junctions in T cells remains poorly understood. Here, we show that junctophilin-4 (JP4), a member of junctional proteins in excitable cells, is expressed in T cells and localized at the ER-PM junctions to regulate Ca2+ signaling. Silencing or genetic manipulation of JP4 decreased ER Ca2+ content and SOCE in T cells, impaired activation of the nuclear factor of activated T cells (NFAT) and extracellular signaling-related kinase (ERK) signaling pathways, and diminished expression of activation markers and cytokines. Mechanistically, JP4 directly interacted with STIM1 via its cytoplasmic domain and facilitated its recruitment into the junctions. Accordingly, expression of this cytoplasmic fragment of JP4 inhibited SOCE. Furthermore, JP4 also formed a complex with junctate, a Ca2+-sensing ER-resident protein, previously shown to mediate STIM1 recruitment into the junctions. We propose that the junctate-JP4 complex located at the junctions cooperatively interacts with STIM1 to maintain ER Ca2+ homeostasis and mediate SOCE in T cells.
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