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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.
Abstract
NAADP-evoked Ca2+ release through type 1 ryanodine receptors (RYR1) is a major mechanism underlying the earliest signals in T cell activation, which are the formation of Ca2+ microdomains. In our characterization of the molecular machinery underlying NAADP action, we identified an NAADP-binding protein, called hematological and neurological expressed 1–like protein (HN1L) [also known as Jupiter microtubule-associated homolog 2 (JPT2)]. Gene deletion of Hn1l/Jpt2 in human Jurkat and primary rat T cells resulted in decreased numbers of initial Ca2+ microdomains and delayed the onset and decreased the amplitude of global Ca2+ signaling. Photoaffinity labeling demonstrated direct binding of NAADP to recombinant HN1L/JPT2. T cell receptor/CD3–dependent coprecipitation of HN1L/JPT2 with RYRs and colocalization of these proteins suggest that HN1L/JPT2 connects NAADP formation with the activation of RYR channels within the first seconds of T cell activation. Thus, HN1L/JPT2 enables NAADP to activate Ca2+ release from the endoplasmic reticulum through RYR.
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