PT  - JOURNAL ARTICLE
AU  - Jiyuan Zhang
AU  - Xin Guan
AU  - Jiusheng Yan
TI  - Lsm12 is an NAADP receptor mediating intracellular calcium mobilization
AID  - 10.1101/2020.05.21.109850
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.21.109850
4099  - http://biorxiv.org/content/early/2020/05/22/2020.05.21.109850.short
4100  - http://biorxiv.org/content/early/2020/05/22/2020.05.21.109850.full
AB  - Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent Ca2+-mobilizing second messenger which uniquely mobilizes Ca2+ from acidic endolysosomal organelles. However, the molecular identity of the NAADP receptor remains unknown. Given that the endolysosomal two-pore channel (TPC) is essential for NAADP-signaling and likely part of the signaling protein complexes, we performed affinity purification and quantitative proteomic analysis of the NAADP signaling complexes. We identified an Sm-like protein Lsm12 that interacts with both NAADP and TPCs. Lsm12 directly binds to NAADP via its Lsm domain, whereas TPC-containing membranes and isolated TPCs lose their affinities to NAADP in the absence of Lsm12. Lsm12 is essential and immediately involved in NAADP-evoked TPC2 activation and intracellular Ca2+ mobilization. This finding reveals a role of a putative RNA-binding protein to function as an NAADP receptor in different cells and provides a molecular basis for understanding the mechanisms of NAADP signaling.Competing Interest StatementThe authors have declared no competing interest.