Abstract
SummaryMembrane 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.
Highlights
How organelles communicate is a fundamental question that arises given the compartmentalized nature of eukaryotic cell function
nicotinic acid adenine dinucleotide phosphate (NAADP) and TPC1 Maintain Late Endosome and Lysosome Morphology We examined the effect of inhibiting NAADP action on late endosome and lysosome morphology in primary human fibroblasts using four approaches
We further examined the ultrastructure of the endo-lysosomal system by electron microscopy (EM)
Summary
How organelles communicate is a fundamental question that arises given the compartmentalized nature of eukaryotic cell function. The endoplasmic reticulum (ER) forms multiple classes of contacts with both the plasma membrane and organelles such as endosomes, lysosomes, and mitochondria. Endosome-ER contacts have been implicated in endosome positioning (Rocha et al, 2009; Raiborg et al, 2015a), dephosphorylation of internalized receptors, and components of the endosomal sorting complex required for transport (ESCRT) machinery (Eden et al, 2010, 2016; Stuible et al, 2010), endosome fission (Rowland et al, 2014), actin nucleation and retromer-dependent budding (Dong et al, 2016), and cholesterol transport (Eden et al, 2016). We have identified multiple populations of contact sites that form between the ER and different endocytic organelles (Eden et al, 2016), which include those dependent on VAPs (Dong et al, 2016). Contact sites between the ER and EGF receptor-containing endosomes require annexin-A1 and its Ca2+-dependent binding partner S100A11 (Eden et al, 2016), raising the possibility that Ca2+ fluxes may regulate contact
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