SLC19A1 is an importer of the immunotransmitter cGAMP.

Ritchie, Christopher; Cordova, Anthony F.; Hess, Gaelen T.; Bassik, Michael C.; Li, Lingyin

doi:10.1016/j.molcel.2019.05.006

Cited by 335interferon and immune responsesPhosphodiesterase function and regulationAdenosine and Purinergic Signaling

SLC19A1 is an importer of the immunotransmitter cGAMP.

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Ritchie, Christopher, Cordova, Anthony F., Hess, Gaelen T., Bassik, Michael C., Li, Lingyin·2019·Molecular Cell

DOI 10.1016/j.molcel.2019.05.006PMC PMC6711396

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Abstract

2'3'-cyclic-GMP-AMP (cGAMP) is a second messenger that activates the antiviral stimulator of interferon genes (STING) pathway. We recently identified a novel role for cGAMP as a soluble, extracellular immunotransmitter that is produced and secreted by cancer cells. Secreted cGAMP is then sensed by host cells, eliciting an antitumoral immune response. Due to the antitumoral effects of cGAMP, other CDN-based STING agonists are currently under investigation in clinical trials for metastatic solid tumors. However, it is unknown how cGAMP and other CDNs cross the cell membrane to activate intracellular STING. Using a genome-wide CRISPR screen, we identified SLC19A1 as the first known importer of cGAMP and other CDNs, including the investigational new drug 2'3'-bisphosphosphothioate-cyclic-di-AMP (2'3'-CDA S). These discoveries will provide insight into cGAMP's role as an immunotransmitter and aid in the development of more targeted CDN-based cancer therapeutics.

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cGAMP is secreted from cancer cells via SLC19A1, which induces activation of the STING pathway in recipient cells.
“Interestingly, cGAMP is also secreted from cancer cells via SLC19A1, which induces activation of the STING pathway in recipient cells.78, 79”
From Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer (2020) · cites this paper as [78]
The Introduction says cancer cells export cGAMP and that it can activate STING in nearby host cells. But the Discussion identifies SLC19A1 as a cGAMP importer, not the route by which cancer cells secrete it. The claimed direction of transport via SLC19A1 is therefore contrary to the source. (LLM, conf=0.90)
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SLC19A1 is first known major importer of cGAMP, taken up by host cells to activate intracellular STING pathway to elicit antitumor immune response.
“Using a genome wide CRISPR interference screen, SLC19A1, was identified as the first known major importer of cGAMP, which is taken up by host cells to activate intracellular STING pathway to elicit an antitumor immune response.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Ritchie et al., 2019
cGAMP is a soluble extracellular immunotransmitter produced and secreted by malignant cells.
“Recently, a novel role of cGAMP as a soluble extracellular immunotransmitter produced and secreted by malignant cells has been identified.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Ritchie et al., 2019

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SLC19A1 is a cyclic dinucleotide transporterPreprint
Luteijn, R. D., Zaver, S. A., Gowen, B. G., Wyman, S. K., Garelis, N. E., Onia, L., McWhirter, S. M., Katibah, G. E., Corn, J. E., Woodward, J. J., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/539767 · Cited by 1 · see citing works
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Self-citation
SLC19A1 transports immunoreactive cyclic dinucleotides.
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In response to Luteijn et al .: Concerns regarding cGAMP uptake assay and evidence that SLC19A1 is not the major cGAMP importer in human PBMCsPreprint
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Self-citation
An alternatively spliced STING isoform localizes in the cytoplasmic membrane and directly senses extracellular cGAMP
Li, X., Zhu, Y., Zhang, X., An, X., Weng, M., Shi, J., Wang, S., Liu, C., Luo, S., & Zheng, T. (2021) · Journal of Clinical Investigation · doi:10.1172/jci144339 · Cited by 35 · see citing works

Authors: Ritchie, C., Cordova, A. F., Hess, G. T., Bassik, M. C., & Li, L.
Affiliations: Stanford University (US)
Stanford Medicine (US)
Corresponding author: Li, Lingyin
ORCID: Ritchie, Christopher
Cordova, Anthony F.
Hess, Gaelen T.
Bassik, Michael C.
Li, Lingyin
Venue: Molecular Cell
Publisher: Elsevier BV
Published: 2019-07
Volume: 75
Issue: 2
Pages: 372-381.e5
ISSN: 1097-2765 (ISSN-L)
DOI: 10.1016/j.molcel.2019.05.006
PMC: PMC6711396
OpenAlex: W2952481556
Cited by: 333
References: 44
Citations by year: 2026: 35 · 2025: 38 · 2024: 49 · 2023: 55 · 2022: 53 · 2021: 46 · 2020: 47 · 2019: 10
FWCI: 15.75
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 390 d)
Locations: Molecular Cell (publishedVersion)
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (5R00CA19089, DP2HD084069, DP2CA228044, 2T32GM007365, 5T32GM007276)
Topics: Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
Keywords: SLC19A1, cGAMP, STING pathway, STING agonist, cancer immunotherapy, membrane transport, antitumor immunity
MeSH terms: STING Protein, Cell Membrane, Humans, Immunity, Innate, Membrane Proteins, Neoplasms, Nucleotides, Cyclic, Signal Transduction, Genome, Human, Cell Line, Tumor, Reduced Folate Carrier Protein, CRISPR-Cas Systems

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SLC19A1 is an importer of the immunotransmitter cGAMP.

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