Jupiter microtubule associated homolog 2
cytosol
HN1L/JPT2: A signaling protein that connects NAADP generation to Ca<sup>2+</sup> microdomain formation.
NAADP-evoked Ca<sup>2+</sup> release through type 1 ryanodine receptors (RYR1) is a major mechanism underlying the earliest signals in T cell activation, which are the formation of Ca<sup>2+</sup> 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 <i>Hn1l/Jpt2</i> in human Jurkat and primary rat T cells resulted in decreased numbers of initial Ca<sup>2+</sup> microdomains and delayed the onset and decreased the amplitude of global Ca<sup>2+</sup> 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 Ca<sup>2+</sup> release from the endoplasmic reticulum through RYR.