Small regulators, major consequences – Ca2+ and cholesterol at the endosome–ER interface

Abstract

The ER is the largest cellular compartment and a major storage site for lipids and ions. In recent years, much attention has focused on contacts between the ER and other organelles, and one particularly intimate relationship is that between the ER and the endosomal system. ER-endosome contacts intensify when endosomes mature, and the ER participates in endosomal processes, such as the termination of surface receptor signaling, multi-vesicular body formation, and transport and fusion events. Cholesterol and Ca 2+ are transferred between the ER and endosomes, possibly acting as messengers for ER-endosome crosstalk. Here, we summarize different types of ER-endosomal communication and discuss membrane contact sites that might facilitate this crosstalk. We review the protein pairs that interact at the ER-endosome interface and find that many of these have a role in cholesterol exchange. We also summarize Ca 2+ exchange between the ER and endosomes, and hypothesize that ERendosome contacts integrate several cellular functions to guide endosomal maturation. We post the hypothesis that failure in ERendosome contacts is an unrecognized but important contributor to diseases, such as Niemann-Pick type C disease, Alzheimer's disease and amyotrophic lateral sclerosis.

A novel Ca2+-mediated cross-talk between endoplasmic reticulum and acidic organelles: Implications for NAADP-dependent Ca2+ signalling

“…This might be realized through an agonist-induced Ca 2+ elevation but might also be via Ca 2+ leakage mechanism, perhaps through constitutively open TPCs, RyRs or InsP 3 Rs. These data suggests that Ca 2+ accumulation within both compartments requires a tight and finely tuned Ca 2+ exchange at the ER-EL interface and builds a new level of complexity to our understanding of control of cellular Ca 2+ homeostasis [60]. Consequently, the blockade of Ca 2+ refilling into either of the two Ca 2+ pools leads to an appreciable decrease in the intraluminal Ca 2+ levels of the other.…”

“…While TPCs have been clearly established to mobilize Ca 2+ from acidic lysosome-like vesicles in sea urchin eggs [58], the target organelle(s) and cognate receptor(s) of NAADP in mammalian cells are far from being clearly elucidated [7,9,[18][19][20]. The controversial issue as to whether NAADP serves as a triggering signal to initiate intracellular Ca 2+ waves by recruiting either InsP 3 Rs and/or RyRs upon lysosomal Ca 2+ release or it directly activates ER-located RyRs has been fuelled by our poor knowledge of the ER-EL Ca 2+ cross-talk [28,59,60]. This deficit in our knowledge of the basic mechanisms of organellar interaction might have biased the interpretation of many data produced by the pharmacological manipulation of the multiple Ca 2+ pools endowed to mammalian cells [61].…”

“…A recent series of elegant studies conducted by three separate groups have, however, unveiled the bidirectional nature of Ca 2+ movements occurring at the ER-EL interface [29,31,60]. In addition of being directly loaded into ER lumen following NAADPdependent TPC activation [4,16,17], Ca 2+ can be sequestered back into EL Ca 2+ stores upon ER-induced Ca 2+ mobilization [29,31,60]. This Ca 2+ -mediated cross-talk between two physically distinct Ca 2+ pools might bias any conclusion drawn based on the selective inhibition of Ca 2+ uptake by each of them.…”

“…This feature might be relevant to the regulation of Ca 2+ -dependent EL functions, such as control of lysosomal pH and enzyme activity, vesicle trafficking and TPC gating [28,31,60], under both physiological and pathological (i.e. Niemann-Pick type C disease, amyotrophic lateral sclerosis and Alzheimer's disease) conditions.…”

ER–endosome contact sites in endosome positioning and protrusion outgrowth

“…binding protein-related protein 1L (ORP1L) and ERassociated VAMP-associated protein (VAP) [2]. ORP1L is anchored to LEs by binding the LE-specific small GTPase Ras-associated protein 7 (Rab7) and its effector Rab Interacting Lysosomal Protein (RILP).…”