TY - JOUR
T1 - Lsm12 is an NAADP receptor and a two-pore channel regulatory protein required for calcium mobilization from acidic organelles
AU - Zhang, Jiyuan
AU - Guan, Xin
AU - Shah, Kunal
AU - Yan, Jiusheng
N1 - Funding Information:
We thank Michael X. Zhu (The University of Texas Health Science Center at Houston) and Youxing Jiang (The University of Texas Southwestern Medical Center) for manuscript reading, discussion, and comments. We thank Meggie Young for assistance in protein purification and all lab members for discussion. Mass spectrometry raw data were collected at the Proteomic Cores of the University of California in Davis and the University of Texas Southwestern Medical Center and Shenzhen Huada Gene Technology Co Ltd. The founder lines of mutant mice were generated at MD Anderson Cancer Center Genetically Engineered Mouse Facility. This work was supported by National Institutes of Health grants NS096296 (J.Y.) and GM130814 (J.Y.).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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 the necessity of the endolysosomal two-pore channel (TPC1 or TPC2) in NAADP signaling, we performed affinity purification and quantitative proteomic analysis of the interacting proteins of NAADP and TPCs. We identified a Sm-like protein Lsm12 complexed with NAADP, TPC1, and TPC2. Lsm12 directly binds to NAADP via its Lsm domain, colocalizes with TPC2, and mediates the apparent association of NAADP to isolated TPC2 or TPC2-containing membranes. Lsm12 is essential and immediately participates in NAADP-evoked TPC activation and Ca2+ mobilization from acidic stores. These findings reveal a putative RNA-binding protein to function as an NAADP receptor and a TPC regulatory protein and provides a molecular basis for understanding the mechanisms of NAADP signaling.
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 the necessity of the endolysosomal two-pore channel (TPC1 or TPC2) in NAADP signaling, we performed affinity purification and quantitative proteomic analysis of the interacting proteins of NAADP and TPCs. We identified a Sm-like protein Lsm12 complexed with NAADP, TPC1, and TPC2. Lsm12 directly binds to NAADP via its Lsm domain, colocalizes with TPC2, and mediates the apparent association of NAADP to isolated TPC2 or TPC2-containing membranes. Lsm12 is essential and immediately participates in NAADP-evoked TPC activation and Ca2+ mobilization from acidic stores. These findings reveal a putative RNA-binding protein to function as an NAADP receptor and a TPC regulatory protein and provides a molecular basis for understanding the mechanisms of NAADP signaling.
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U2 - 10.1038/s41467-021-24735-z
DO - 10.1038/s41467-021-24735-z
M3 - Article
C2 - 34362892
AN - SCOPUS:85112489422
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4739
ER -