An Endosomal NAADP-Sensitive Two-Pore Ca 2+ Channel Regulates ER-Endosome Membrane Contact Sites to Control Growth Factor Signaling

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.

Integration of nicotinic acid adenine dinucleotide phosphate (NAADP)‐dependent calcium signalling

“…Interestingly, NAADP signalling has been shown to regulate the signal strength of epidermal growth factor (EGF) receptor signalling in a negative fashion (Kilpatrick et al . ).…”

Vacuole membrane protein 1 marks endoplasmic reticulum subdomains enriched in phospholipid synthesizing enzymes and is required for phosphoinositide distribution

“…Recently, several publications highlighted the important role of MCSs between ER and endosomes in endosome maturation . Because VMP1‐GFP marks distinct ER subdomains associated with endosomes, we aimed to further characterize the association of VMP1 with these organelles.…”

Lysosomal Calcium in Neurodegeneration

“…Inhibition of IP3Rs caused lysosome dysfunction and LSD-like phenotype. Furthermore, the critical role of ER for lysosomal calcium refilling is also supported by the intimate spatial localization of ER and lysosomes (also see (Kilpatrick et al, 2013; Aston et al, 2017; Kilpatrick et al, 2017)). Overall, this new study provided a new platform to study the mechanism of lysosomal Ca 2+ refilling.…”

“…ER-lysosome contact sites are still poorly understood in mammalian cells (Kilpatrick et al, 2013; Kilpatrick et al, 2017). The yeast counterparts, ER-vacuole contact sites, are much more clearly defined in the involving players, which may therefore shed light on disorders caused by mutation in their human homolog genes (Hariri et al, 2016).…”