IP3 Receptors Preferentially Associate with ER-Lysosome Contact Sites and Selectively Deliver Ca2+ to Lysosomes

• Published in: Cell reports (Cambridge) 2018-12, Vol.25 (11), p.3180-3193.e7
• Main Authors: Atakpa, Peace, Thillaiappan, Nagendra Babu, Mataragka, Stefania, Prole, David L., Taylor, Colin W.
• Format: Article
• Language: English
• Subjects: Ca2; concanamycin A; endoplasmic reticulum; genetically encoded Ca2+ sensor; IP3 receptor; lysosome; membrane contact site; proximity ligation assay; store-operated Ca2+ entry
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.11.064

Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) allow extracellular stimuli to redistribute Ca2+ from the ER to cytosol or other organelles. We show, using small interfering RNA (siRNA) and vacuolar H+-ATPase (V-ATPase) inhibitors, that lysosomes sequester Ca2+ released by all IP3R subtypes, but not Ca2+ entering cells through store-operated Ca2+ entry (SOCE). A low-affinity Ca2+ sensor targeted to lysosomal membranes reports large, local increases in cytosolic [Ca2+] during IP3-evoked Ca2+ release, but not during SOCE. Most lysosomes associate with endoplasmic reticulum (ER) and dwell at regions populated by IP3R clusters, but IP3Rs do not assemble ER-lysosome contacts. Increasing lysosomal pH does not immediately prevent Ca2+ uptake, but it causes lysosomes to slowly redistribute and enlarge, reduces their association with IP3Rs, and disrupts Ca2+ exchange with ER. In a “piston-like” fashion, ER concentrates cytosolic Ca2+ and delivers it, through large-conductance IP3Rs, to a low-affinity lysosomal uptake system. The involvement of IP3Rs allows extracellular stimuli to regulate Ca2+ exchange between the ER and lysosomes. [Display omitted] •IP3 receptors (IP3Rs) selectively deliver Ca2+ to lysosomes•Lysosomes associate preferentially with clusters of IP3Rs in ER membranes•Low lysosomal pH maintains the IP3R-lysosome contacts required for Ca2+ uptake•ER and its Ca2+ channels deliver Ca2+ to low-affinity lysosomal transporters Ca2+ exchanges between ER and lysosomes regulate cytosolic Ca2+ signals and lysosome behavior. Atakpa et al. show that clusters of IP3 receptors populate ER-lysosome contact sites and facilitate local delivery of Ca2+ from the ER to lysosomes.