Department of Anesthesiology & Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Neuroscience and Biochemistry & Cell Biology Programs, The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX, USA.
Nat Commun. 2021 Aug 6;12(1):4739. doi: 10.1038/s41467-021-24735-z.
Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent Ca-mobilizing second messenger which uniquely mobilizes Ca 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 Ca 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.
烟酰胺腺嘌呤二核苷酸磷酸（NAADP）是一种强效的 Ca2+动员第二信使，它能特异性地从酸性内涵体/溶酶体细胞器中动员 Ca2+。然而，NAADP 受体的分子身份仍然未知。鉴于内涵体双孔通道（TPC1 或 TPC2）在 NAADP 信号转导中的必要性，我们对 NAADP 和 TPCs 的相互作用蛋白进行了亲和纯化和定量蛋白质组学分析。我们鉴定出一个 Sm 样蛋白 Lsm12 与 NAADP、TPC1 和 TPC2 复合物。Lsm12 通过其 Lsm 结构域直接与 NAADP 结合，与 TPC2 共定位，并介导 NAADP 与分离的 TPC2 或含有 TPC2 的膜的明显结合。Lsm12 是必需的，并立即参与 NAADP 诱导的 TPC 激活和 Ca2+从酸性储存库中动员。这些发现揭示了一种假定的 RNA 结合蛋白作为 NAADP 受体和 TPC 调节蛋白的功能，并为理解 NAADP 信号转导的机制提供了分子基础。
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