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SLC19A1 transports immunoreactive cyclic dinucleotides.
Nature 2019; 573(7774):434-438Nat

Abstract

The accumulation of DNA in the cytosol serves as a key immunostimulatory signal associated with infections, cancer and genomic damage1,2. Cytosolic DNA triggers immune responses by activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway3. 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 STING8, 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 cells9 and other CDNs, including those produced by bacteria10-12 and synthetic CDNs used in cancer immunotherapy13,14, 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 cancer13, host responsiveness to CDN-producing pathogenic microorganisms11 and-potentially-for some inflammatory diseases.

Authors+Show Affiliations

Department of Molecular and Cell Biology, and Cancer Research Laboratory, Division of Immunology and Pathogenesis, University of California, Berkeley, CA, USA.Department of Microbiology, University of Washington, Seattle, WA, USA.Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.Department of Molecular and Cell Biology, and Cancer Research Laboratory, Division of Immunology and Pathogenesis, University of California, Berkeley, CA, USA.Department of Molecular and Cell Biology, and Cancer Research Laboratory, Division of Immunology and Pathogenesis, University of California, Berkeley, CA, USA.Aduro Biotech, Berkeley, CA, USA.Aduro Biotech, Berkeley, CA, USA.Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA. Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.Department of Microbiology, University of Washington, Seattle, WA, USA.Department of Molecular and Cell Biology, and Cancer Research Laboratory, Division of Immunology and Pathogenesis, University of California, Berkeley, CA, USA. raulet@berkeley.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31511694

Citation

Luteijn, Rutger D., et al. "SLC19A1 Transports Immunoreactive Cyclic Dinucleotides." Nature, vol. 573, no. 7774, 2019, pp. 434-438.
Luteijn RD, Zaver SA, Gowen BG, et al. SLC19A1 transports immunoreactive cyclic dinucleotides. Nature. 2019;573(7774):434-438.
Luteijn, R. D., Zaver, S. A., Gowen, B. G., Wyman, S. K., Garelis, N. E., Onia, L., ... Raulet, D. H. (2019). SLC19A1 transports immunoreactive cyclic dinucleotides. Nature, 573(7774), pp. 434-438. doi:10.1038/s41586-019-1553-0.
Luteijn RD, et al. SLC19A1 Transports Immunoreactive Cyclic Dinucleotides. Nature. 2019;573(7774):434-438. PubMed PMID: 31511694.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SLC19A1 transports immunoreactive cyclic dinucleotides. AU - Luteijn,Rutger D, AU - Zaver,Shivam A, AU - Gowen,Benjamin G, AU - Wyman,Stacia K, AU - Garelis,Nick E, AU - Onia,Liberty, AU - McWhirter,Sarah M, AU - Katibah,George E, AU - Corn,Jacob E, AU - Woodward,Joshua J, AU - Raulet,David H, Y1 - 2019/09/11/ PY - 2018/11/21/received PY - 2019/08/08/accepted PY - 2019/9/13/pubmed PY - 2019/9/13/medline PY - 2019/9/13/entrez SP - 434 EP - 438 JF - Nature JO - Nature VL - 573 IS - 7774 N2 - The accumulation of DNA in the cytosol serves as a key immunostimulatory signal associated with infections, cancer and genomic damage1,2. Cytosolic DNA triggers immune responses by activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway3. 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 STING8, 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 cells9 and other CDNs, including those produced by bacteria10-12 and synthetic CDNs used in cancer immunotherapy13,14, 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 cancer13, host responsiveness to CDN-producing pathogenic microorganisms11 and-potentially-for some inflammatory diseases. SN - 1476-4687 UR - https://www.unboundmedicine.com/medline/citation/31511694/SLC19A1_transports_immunoreactive_cyclic_dinucleotides L2 - https://doi.org/10.1038/s41586-019-1553-0 DB - PRIME DP - Unbound Medicine ER -