SMPDL3A is a cGAMP-degrading enzyme induced by LXR-mediated lipid metabolism to restrict cGAS-STING DNA sensing

Hou, Yanfei; Wang, Zhimeng; Liu, Peiyuan; Wei, Xubiao; Zhang, Zhengyin; Fan, Shilong; Zhang, Lulu; Han, Fangping; Song, Yikang; Chu, Ling; Zhang, Conggang

doi:10.1016/j.immuni.2023.10.001

Cited by 19 publications

(6 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mn 2+ acts on the cGAS−STING pathway, and to further elucidate the mechanism, key proteins and phosphorylated proteins in the cGAS−STING pathway were analyzed, with results presented in Figures 4J,K and S12A,B. 31 The trends observed in protein expression in the cGAS−STING pathway in both BMDCs and BMDMs were consistent. It is evident that protein band expression increased after treatment in various groups, with 177 Lu/Mn-HAP demonstrating the most substantial enhancement in protein expression, indicating the most significant activation of the signaling pathway.…”

Section: Resultsmentioning

confidence: 80%

“…The most substantial effect was observed when antigens were involved, confirming the adjuvant role of Mn 2+ . Mn 2+ acts on the cGAS–STING pathway, and to further elucidate the mechanism, key proteins and phosphorylated proteins in the cGAS–STING pathway were analyzed, with results presented in Figures J,K and S12A,B . The trends observed in protein expression in the cGAS–STING pathway in both BMDCs and BMDMs were consistent.…”

Section: Resultsmentioning

confidence: 80%

See 1 more Smart Citation

Radioactive Hydroxyapatite Microspheres Empower Sustainable In Situ Tumor Vaccination

Xu,

Gu,

et al. 2024

ACS Nano

View full text Add to dashboard Cite

Tumor in situ vaccination (ISV) strategies have emerged in clinical trials as promising approaches, involving the release of tumor antigens through local radiotherapy and intratumorally adjuvant injections. However, the current fabrication strategy for achieving a sustainable immune response to ISV remains a pressing challenge. In this study, we present an empowered sustainable ISV method for antitumor therapy using 177 Lu-labeled manganesedoped mesoporous hydroxyapatite ( 177 Lu/Mn-HAP) microspheres. The ISV enables the sustained utilization of tumor antigens, leading to the activation of dendritic cells and polarization of macrophages toward the M1 subtype. Consequently, it facilitates the generation of potent CD8 + T-cell responses, enhancing the antitumor effects of internal radiation in both primary and distant tumors. Importantly, this approach achieves complete remission in all tumorbearing mice and stimulates immune memory to prevent tumor recurrence. Our study highlights a universal and safe ISV strategy capable of inducing potent tumor-specific and sustainable immune response.

show abstract

Section: Resultsmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 80%

Radioactive Hydroxyapatite Microspheres Empower Sustainable In Situ Tumor Vaccination

Xu,

Gu,

et al. 2024

ACS Nano

View full text Add to dashboard Cite

show abstract

“…The hydrolysis of 2’,3’-cGAMP is a well-known activity of human ENPP1 (Borza et al 2021; Kato et al 2018; Li et al 2014; Ritchie et al 2022). However, while this work was in progress, this activity was also described for human SMPDL3A (ASM3A_HUMAN, acid sphingomyelinase-like phosphodiesterase 3a) (Hou et al 2023) and for human ENPP3 (Mardjuki et al 2024). Like RLNPP/PDE, these three proteins are also active against ATP and 4-nitrophenyl-dTMP.…”

Section: Resultsmentioning

confidence: 94%

Free Amino Acids Accelerate the Time-Dependent Inactivation of Rat Liver Nucleotide Pyrophosphatase / Phosphodiesterase Enpp3 elicited by EDTA

Romero,

Cumplido-Laso,

Fernández

et al. 2024

Preprint

View full text Add to dashboard Cite

Nucleotide-pyrophosphatases/phosphodiesterases (NPP/PDE) are membrane or secreted Zn2+-metallohydrolases of nucleoside-5’-monophosphate derivatives. They hydrolyze, for instance, ATP and 4-nitrophenyl-dTMP, and belong to the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family that contains seven members (ENPP1-ENPP7). Earlier we had shown that an NPP/PDE activity solubilized and partially purified from rat liver membranes is inactivated by EDTA in a time-dependent fashion, an effect enhanced by glycine and blocked by the 4-nitrophenyl-dTMP. Here, we extended this observation to other free amino acids. Activity assays started after different incubation lengths with EDTA provided first-order, apparent inactivation constants (ki(ap)). With the exception of cysteine (a strong inhibitor) and histidine (itself evoking a time-dependent inactivation), free amino acids themselves did not affect activity but increased ki(ap). The results are compatible with a conformational change of NPP/PDE evoked by interaction with free amino acids. The enzyme preparation was analyzed to identify what ENPP family members were present. First, the hydrolytic activity on 2’,3’-cGAMP was assayed because until very recently ENPP1 was the only mammalian enzyme known to display it. 2’,3’-cGAMP hydrolase activity was clearly detected, but mass spectrometry data obtained by LC-MS/MS gave evidence that only rat Enpp3, Enpp4 and Enpp5 were present with low abundance. This finding coincided in time with a recent publication claiming that mouse Enpp3 hydrolyzes 2’,3’-cGAMP, and that Enpp1 and Enpp3 account for all the 2’,3’-cGAMP hydrolase activity in mice. So, our results are confirmatory of Enpp3 activity towards 2’,3’-cGAMP. Finally, the effect of amino acids could be relevant to NPP/PDE actions dependent on protein-protein interactions, like the known insulin-related effects of ENPP1 and possibly ENPP3.

show abstract

“…We cannot rule out the possibility that other cGAMP hydrolases, intracellular or extracellular, could be induced or activated upon detection of a pathogen or other stimulus. Indeed, while this paper was under review, the discovery of SMPDL3A, a third cGAMP hydrolase, was reported 38 . SMPDL3A is a secreted enzyme whose expression is induced by liver X receptor ligands.…”

Section: Discussionmentioning

confidence: 99%

Identification of extracellular membrane protein ENPP3 as a major cGAMP hydrolase, cementing cGAMP’s role as an immunotransmitter

Mardjuki,

Wang,

Carozza

et al. 2024

Preprint

View full text Add to dashboard Cite

cGAMP is a second messenger that is synthesized in the cytosol upon detection of cytosolic dsDNA and passed between cells to facilitate downstream immune signaling. ENPP1, an extracellular enzyme, was the only metazoan cGAMP hydrolase known to regulate cGAMP levels to dampen anti-cancer immunity. Here, we uncover ENPP3 as the second and only other metazoan cGAMP hydrolase under homeostatic conditions. ENPP3 has a tissue expression pattern distinct from that of ENPP1 and accounts for all remaining cGAMP hydrolysis activity in mice lacking ENPP1. Importantly, we also show that as with ENPP1, selectively abolishing ENPP3's cGAMP hydrolase activity results in diminished cancer growth and metastasis of certain tumor types. Both ENPP1 and ENPP3 are extracellular enzymes, suggesting the dominant role that extracellular cGAMP must play as a mediator of cell-cell innate immune communication. Our work clearly shows that ENPP1 and ENPP3 non-redundantly dampen extracellular cGAMP-STING signaling, pointing to ENPP3 as a new target for cancer immunotherapy.

show abstract

SMPDL3A is a cGAMP-degrading enzyme induced by LXR-mediated lipid metabolism to restrict cGAS-STING DNA sensing

Cited by 19 publications

References 68 publications

Radioactive Hydroxyapatite Microspheres Empower Sustainable In Situ Tumor Vaccination

Radioactive Hydroxyapatite Microspheres Empower Sustainable In Situ Tumor Vaccination

Free Amino Acids Accelerate the Time-Dependent Inactivation of Rat Liver Nucleotide Pyrophosphatase / Phosphodiesterase Enpp3 elicited by EDTA

Identification of extracellular membrane protein ENPP3 as a major cGAMP hydrolase, cementing cGAMP’s role as an immunotransmitter

Contact Info

Product

Resources

About