Journal
CELL REPORTS
Volume 18, Issue 7, Pages 1636-1645Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.01.052
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Funding
- BBSRC [BB/N01524X/1]
- Parkinson's UK [H-1202]
- MRC [G0801878, M010767]
- Wellcome Trust [093445]
- BBSRC [BB/K000942/1, BB/G013721/1, BB/N01524X/1] Funding Source: UKRI
- MRC [MR/M010767/1, G0801878] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/G013721/1, BB/N01524X/1, BB/K000942/1] Funding Source: researchfish
- Medical Research Council [G0801878, MR/M010767/1] Funding Source: researchfish
- Parkinson's UK [K-1107, K-1412, H-1202] Funding Source: researchfish
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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.
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