8.A.242.  The NAADP-binding Protein (JPT2) Family 

The nicotinic acid-adenine dinucleotide phosphate (NAADP) binding protein JPT2, is, together with another small cytoplasmic protein of the same size, LSM12 (see TC Family 8.A.243), required for NAADP-evoked intracellular calcium release (Gunaratne et al. 2021). These proteins confer NAADP-sensitivity to the two pore channel (TPC) complexes (Gunaratne et al. 2021) and enable NAADP to activate Ca²⁺ release from the endoplasmic reticulum through ryanodine receptors (Roggenkamp et al. 2021). They are also involved in the endolysosomal trafficking of human coronavirus SARS-CoV-2.  NAADP evokes Ca²⁺ release from endosomes and lysosomes by activating two-pore channels (TPCs) in these organelles. Rather than directly binding to TPCs, NAADP associates with the JPT2 and LSM12 proteins that indirectly confer NAADP sensitivity to the TPC complex. Gunaratne et al. 2023 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 results revealed that the NAADP-binding proteins JPT2 and LSM12 convergently regulate NAADP-evoked Ca²⁺ release and function through TPCs (Gunaratne et al. 2023).