Research ArticleCalcium signaling

Essential requirement for JPT2 in NAADP-evoked Ca2+ signaling

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Science Signaling  23 Mar 2021:
Vol. 14, Issue 675, eabd5605
DOI: 10.1126/scisignal.abd5605

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Connecting Ca2+ channels with NAADP

Although generation of the second messenger NAADP stimulates the release of Ca2+ from intracellular stores, binding sites for NAADP have not been characterized on NAADP-sensitive ion channels. Two papers independently identified an NAADP-binding protein called HN1L, which is also known as JPT2, that interacts with ryanodine receptors in the endoplasmic reticulum in T cells and two-pore channels (TPCs) in endosomes and lysosomes. Roggenkamp et al. found that HN1L deletion suppressed the formation of Ca2+ microdomains in stimulated Jurkat and primary rat T cells, one of the earliest responses to T cell receptor activation, thereby reducing global Ca2+ signaling. Gunaratne et al. found that knockdown of JPT2 attenuated NAADP-evoked Ca2+ signals from endosomes and lysosomes and the ability of a SARS-CoV-2 pseudocoronavirus to infect cells, a process that depends on TPC activity. Thus, HN1L/JPT2 enables NAADP to activate Ca2+ release from the endoplasmic reticulum through ryanodine receptors and from endosomes and lysosomes through TPCs.


Nicotinic acid adenine dinucleotide phosphate (NAADP) is a second messenger that releases Ca2+ from acidic organelles through the activation of two-pore channels (TPCs) to regulate endolysosomal trafficking events. NAADP action is mediated by NAADP-binding protein(s) of unknown identity that confer NAADP sensitivity to TPCs. Here, we used a “clickable” NAADP-based photoprobe to isolate human NAADP-binding proteins and identified Jupiter microtubule-associated homolog 2 (JPT2) as a TPC accessory protein required for endogenous NAADP-evoked Ca2+ signaling. JPT2 was also required for the translocation of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus through the endolysosomal system. Thus, JPT2 is a component of the NAADP receptor complex that is essential for TPC-dependent Ca2+ signaling and control of coronaviral entry.

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