An Endosomal NAADP-Sensitive Two-Pore Ca
| Autor: | Bethan S, Kilpatrick, Emily R, Eden, Leanne N, Hockey, Elizabeth, Yates, Clare E, Futter, Sandip, Patel |
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| Rok vydání: | 2016 |
| Předmět: | |
| Zdroj: | Cell Reports |
| ISSN: | 2211-1247 |
| Popis: | Summary Membrane contact sites are regions of close apposition between organelles that facilitate information transfer. Here, we reveal an essential role for Ca2+ derived from the endo-lysosomal system in maintaining contact between endosomes and the endoplasmic reticulum (ER). Antagonizing action of the Ca2+-mobilizing messenger NAADP, inhibiting its target endo-lysosomal ion channel, TPC1, and buffering local Ca2+ fluxes all clustered and enlarged late endosomes/lysosomes. We show that TPC1 localizes to ER-endosome contact sites and is required for their formation. Reducing NAADP-dependent contacts delayed EGF receptor de-phosphorylation consistent with close apposition of endocytosed receptors with the ER-localized phosphatase PTP1B. In accord, downstream MAP kinase activation and mobilization of ER Ca2+ stores by EGF were exaggerated upon NAADP blockade. Membrane contact sites between endosomes and the ER thus emerge as Ca2+-dependent hubs for signaling. Graphical Abstract Highlights • NAADP/TPC1 signaling maintains endo-lysosomal morphology • TPC1 localizes to contacts between late endosomes and the endoplasmic reticulum • NAADP/TPC1 signaling regulates contact site formation • NAADP tempers EGF receptor-mediated signaling Endosomes form junctions with the ER, but how this contact is regulated remains unclear. Kilpatrick et al. find that Ca2+ release by an endosomal ion channel facilitates inter-organellar coupling to temper signals mediated by an internalized growth factor receptor. Endosome-ER contact sites thus emerge as Ca2+-dependent signaling hubs. |
| Databáze: | OpenAIRE |
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