SLC19A1 transports immunoreactive cyclic dinucleotides.
Open accessAbstract
The accumulation of DNA in the cytosol serves as a key immunostimulatory signal associated with infections, cancer and genomic damage 1,2. Cytosolic DNA triggers immune responses by activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway 3. The binding of DNA to cGAS activates its enzymatic activity, leading to the synthesis of a second messenger, cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP)4-7. This cyclic dinucleotide (CDN) activates STING 8, which in turn activates the transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), promoting the transcription of genes encoding type I interferons and other cytokines and mediators that stimulate a broader immune response. Exogenous 2'3'-cGAMP produced by malignant cells 9 and other CDNs, including those produced by bacteria 10-12 and synthetic CDNs used in cancer immunotherapy 13,14, must traverse the cell membrane to activate STING in target cells. How these charged CDNs pass through the lipid bilayer is unknown. Here we used a genome-wide CRISPR-interference screen to identify the reduced folate carrier SLC19A1, a folate-organic phosphate antiporter, as the major transporter of CDNs. Depleting SLC19A1 in human cells inhibits CDN uptake and functional responses, and overexpressing SLC19A1 increases both uptake and functional responses. In human cell lines and primary cells ex vivo, CDN uptake is inhibited by folates as well as two medications approved for treatment of inflammatory diseases, sulfasalazine and the antifolate methotrexate. The identification of SLC19A1 as the major transporter of CDNs into cells has implications for the immunotherapeutic treatment of cancer 13, host responsiveness to CDN-producing pathogenic microorganisms 11 and-potentially-for some inflammatory diseases.
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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 [79]
The paper says that cGAMP produced by malignant cells can activate STING in target cells, and that SLC19A1 mediates cGAMP uptake into human cells (Abstract, page not available). It does not show that cancer cells secrete cGAMP via SLC19A1; the transport it establishes is import into recipient cells. (LLM, conf=0.90)
Experimental — accuracy not yet measuredcGAMP 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 Luteijn et al., 2019
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 Luteijn et al., 2019
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- Authors
- 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., & Raulet, D. H.
- Affiliations
- University of California, Berkeley (US)
- University of Washington (US)
- Innovative Genomics Institute (US)
- Aduro BioTech (United States) (US)
- ETH Zurich (CH)
- Corresponding author
- Raulet, David H.
- ORCID
- Venue
- Nature
- Published
- 2019-09-11
- Volume
- 573
- Issue
- 7774
- Pages
- 434-438
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6785039
- OpenAlex
- W2972961341
- Cited by
- 379
- References
- 47
- Citations by year
- 2026: 25 · 2025: 65 · 2024: 62 · 2023: 50 · 2022: 70 · 2021: 48 · 2020: 51 · 2019: 8
- FWCI
- 17.98
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-03-07)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (1s10od018174-01, 1dp2hl141006-01)
- National Heart, Lung, and Blood Institute (DP2-HL-141006)
- National Cancer Institute (R01CA093678)
- National Institute of General Medical Sciences (T32GM007266)
- National Institute of Allergy and Infectious Diseases (R21AI137758, R01AI113041, T32AI083203, R56AI113041)
- National Center for Research Resources (S10RR029668, S10RR027303)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Keywords
- SLC19A1, reduced folate carrier, cyclic dinucleotides, 2'-3'-cGAMP, STING activation, cGAS-STING pathway, cytosolic DNA sensing, folate transport, membrane transport, sulfasalazine, methotrexate, cancer immunotherapy, innate immunity, inflammatory diseases
- MeSH terms
- Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, Cytosol, DNA, Humans, Inflammation, Nucleotides, Cyclic, Nucleotidyltransferases, Interferon Regulatory Factor-3, Reduced Folate Carrier Protein
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