Lsm12 is an NAADP receptor and a two-pore channel regulatory protein required for calcium mobilization from acidic organelles

Zhang, Jiyuan; Guan, Xin; Shah, Kunal R.; Yan, Jiusheng

doi:10.1038/s41467-021-24735-z

Cited by 59 publications

(55 citation statements)

References 40 publications

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“…YM201636 has anti-viral activity 32,40 , and TPC2 also matters for virus entry 30,32 signaling, it can also be activated by other mechanisms, e.g., by NAADP via Lsm12 for TPC-mediated Ca 2+ mobilization 18 . Therefore, direct blockade of TPC2 by YM201636 can have a more profound effect than that caused by a reduction in PI (3,5)P2 synthesis via inhibition of PIKfyve activity.…”

Section: Discussionmentioning

confidence: 99%

“…The endolysosomal TPCs regulate the function of the endolysosomal system, including endomembrane dynamics and Ca 2+ homeostasis of the acidic stores 3,11 . Accumulating evidence supports that TPCs are critical to NAADP-evoked Ca 2+ release from acidic stores 1,[12][13][14][15][16][17][18] . TPCs are involved in many cellular processes, including autophagy 19 , migration and proliferation of cancer cells 20,21 , muscle cell differentiation 22 and contraction 16 , and fertilization 23 , and they are implicated in pigmentation [24][25][26] , Parkinson's disease 27 , and fatty liver disease 28,29 .…”

Section: Introductionmentioning

confidence: 99%

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Two-pore channel blockade by phosphoinositide kinase inhibitors YM201636 and PI-103 determined by a histidine residue near pore-entrance

Yan

Guan

2022

Preprint

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Human two-pore channels (TPCs) are endolysosomal cation channels and play an important role in NAADP-evoked Ca2+ release and endomembrane dynamics. TPCs are activated by PI(3,5)P2, which is synthesized by PIKfyve. Here, we found that YM201636, a widely used PIKfyve inhibitor, potently inhibits PI(3,5)P2-induced human TPC2 channel Na+ currents in a dose-dependent manner with an IC50 of 0.16 μM. YM201636 also effectively inhibits the currents of a constitutively open TPC2 mutant channel, whereas it exerts no effect when applied in the channel's closed state. A YM201636 analog, PI-103, an inhibitor of PI3K and mTOR, also inhibits human TPC2 with an IC50 of 0.64 μM. Substitution of the pore-constriction residues Leu690, Leu694 and Tyr312 by Ala reduced the effectiveness of YM201636 and PI-103 in channel inhibition. Interestingly, a His699 residue located near the cytosolic pore entrance is a key determinant for the TPC2 channels' sensitivity to YM201636 and PI-103, whose substitution with a Phe in the human TPC1 largely accounts for the channel's loss of inhibition by YM201636. Molecular dynamic simulation and docking analysis of YM201636's binding to TPC2 indicated that His699 can interact with the inhibitor and facilitate the channel-blockade at the cytosolic end of the pore. We conclude that YM201636 and PI-103 directly block the TPC2's open-state channel pore at the cytosolic entrance where the His699 is a key determinant for the blockers' access to the pore. These findings identify two new potent TPC2 channel blockers, reveal a channel pore entrance blockade mechanism, and provide a new protein target in interpreting the pharmacological effects of these two widely used phosphoinositide kinase inhibitors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Two-pore channel blockade by phosphoinositide kinase inhibitors YM201636 and PI-103 determined by a histidine residue near pore-entrance

Yan

Guan

2022

Preprint

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“…It is possible that other NAADP binding proteins exist and participate in NAADP signalsome. Zhang et al have identified Lsm12 as a high affinity NAADP binding protein that is essential for NAADP -induced TPC2 activation (54). The Lsm12 data suggest that NAADP signaling has more components that need to be identified and studied.…”

Section: Discussion and Outlookmentioning

confidence: 99%

NAADP: From Discovery to Mechanism

Walseth

Guse

2021

Front. Immunol.

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Nicotinic acid adenine dinucleotide 2’-phosphate (NAADP) is a naturally occurring nucleotide that has been shown to be involved in the release of Ca2+ from intracellular stores in a wide variety of cell types, tissues and organisms. Current evidence suggests that NAADP may function as a trigger to initiate a Ca2+ signal that is then amplified by other Ca2+ release mechanisms. A fundamental question that remains unanswered is the identity of the NAADP receptor. Our recent studies have identified HN1L/JPT2 as a high affinity NAADP binding protein that is essential for the modulation of Ca2+ channels.

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“…Additionally, a previous study by Zhang et al. also identified LSM12 as an NAADP receptor essential for NAADP-evoked TPC activation and Ca2 + transportation from intracellular acidic stores ( 11 ). The oncologic roles of LSM family members have also been identified in several tumor types ( 12 – 14 ).…”

Section: Introductionmentioning

confidence: 97%

Identification of LSM Family Members as Novel Unfavorable Biomarkers in Hepatocellular Carcinoma

et al. 2022

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BackgroundSmith-like (LSM) family members play critical roles in multiple oncologic processes in several types of malignancies. The study on LSM family members of HCC might provide new insights into the tumorigenesis and therapeutic strategies of HCC.MethodsThe clinical significance and oncologic biological functions of LSM family members were assessed through multiple bioinformatics methods and in vitro studies. The potential correlation between LSM family members and tumor immunity was also investigated using single sample gene set enrichment analysis (ssGSEA) and the ESTIMATE algorithm.ResultsLSM family member overexpression in HCC was significantly correlated with poor clinical outcomes such as higher TNM stage, advanced histologic grade, and worse prognosis. A risk score system based on LSM5, LSM10, LSM12, and LSM14B showed a reliable predictive ability for OS of HCC patients. Functional enrichment analysis demonstrated that LSM family members overexpressed were all involved in cell cycle related biological processes. Besides, LSM12, LSM14A, and LSM14B were found to be significantly associated with PI3K-Akt-mTOR and T cell receptor signaling pathways. Tumors with LSM12, LSM14A, and LSM14B overexpression exhibited lower infiltration of activated CD8+ T cells with declined cytolytic activity and immune score, but increased infiltration of Th2 cells and Th2/Th1. LSM12, LSM14A, and LSM14B overexpression is also associated with higher tumor-related immune checkpoints (e.g., PD-L1, B7-H3, and PVR) expression and increased therapeutic insensitivity to immune checkpoint blockade (ICB). Moreover, the knockdown of LSM12, LSM14A, and LSM14B significantly inhibited the proliferation and invasion of HCC cells.ConclusionThis study systematically investigated the expression pattern and biological values of LSM family members in HCC and identified LSM family members as novel therapeutic targets in HCC.

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Lsm12 is an NAADP receptor and a two-pore channel regulatory protein required for calcium mobilization from acidic organelles

Cited by 59 publications

References 40 publications

Two-pore channel blockade by phosphoinositide kinase inhibitors YM201636 and PI-103 determined by a histidine residue near pore-entrance

Two-pore channel blockade by phosphoinositide kinase inhibitors YM201636 and PI-103 determined by a histidine residue near pore-entrance

NAADP: From Discovery to Mechanism

Identification of LSM Family Members as Novel Unfavorable Biomarkers in Hepatocellular Carcinoma

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