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- Title
Convergent activation of two-pore channels mediated by the NAADP-binding proteins JPT2 and LSM12.
- Authors
Gunaratne, Gihan S.; Brailoiu, Eugen; Kumar, Sushil; Yuan, Yu; Slama, James T.; Walseth, Timothy F.; Patel, Sandip; Marchant, Jonathan S.
- Abstract
The second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) evokes calcium ion (Ca2+) release from endosomes and lysosomes by activating two-pore channels (TPCs) on these organelles. Rather than directly binding to TPCs, NAADP associates with proteins that indirectly confer NAADP sensitivity to the TPC complex. We investigated whether and how the NAADP-binding proteins Jupiter microtubule–associated homolog 2 (JPT2) and like-Sm protein 12 (LSM12) contributed to NAADP-TPC-Ca2+ signaling in human cells. Biochemical and functional analyses revealed that recombinant JPT2 and LSM12 both bound to NAADP with high affinity and that endogenous JPT2 and LSM12 independently associated with TPC1 and TPC2. On the basis of knockout and rescue analyses, both NAADP-binding proteins were required to support NAADP-evoked Ca2+ signaling and contributed to endolysosomal trafficking of pseudotyped coronavirus particles. These data reveal that the NAADP-binding proteins JPT2 and LSM12 convergently regulate NAADP-evoked Ca2+ release and function through TPCs. Editor's summary: The second messenger NAADP indirectly stimulates the opening of two-pore channels (TPCs) on endosomes and lysosomes, thus triggering the release of Ca2+ from these acidic organelles. Gunaratne et al. found that the NAADP-binding proteins JPT2 and LSM12 were both required for NAADP-evoked Ca2+ release and interacted with TPCs in mammalian cells. JPT2 and LSM12 also contributed to the intracellular trafficking of pseudoviruses through endolysosomes, a TPC-dependent process. These findings identify JPT2 and LSM12 as non-redundant factors that mediate NAADP-evoked opening of TPCs. —Annalisa M. VanHook
- Subjects
CALCIUM ions; MICROTUBULE-associated proteins; NIACIN; PROTEINS; LYSOSOMES; ANAPLASTIC lymphoma kinase
- Publication
Science Signaling, 2023, Vol 16, Issue 799, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.adg0485