SLC19A1 transports immunoreactive cyclic dinucleotides

Rutger D. Luteijn, Shivam A. Zaver, Benjamin G. Gowen, Stacia K. Wyman, Nick E. Garelis, Liberty Onia, Sarah M. McWhirter, George E. Katibah, Jacob E. Corn, Joshua J. Woodward and David H. Raulet ()
Additional contact information
Rutger D. Luteijn: University of California
Shivam A. Zaver: University of Washington
Benjamin G. Gowen: University of California, Berkeley
Stacia K. Wyman: University of California, Berkeley
Nick E. Garelis: University of California
Liberty Onia: University of California
Sarah M. McWhirter: Aduro Biotech
George E. Katibah: Aduro Biotech
Jacob E. Corn: University of California, Berkeley
Joshua J. Woodward: University of Washington
David H. Raulet: University of California

Nature, 2019, vol. 573, issue 7774, 434-438

Abstract: 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.

Date: 2019
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-019-1553-0 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:573:y:2019:i:7774:d:10.1038_s41586-019-1553-0

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-019-1553-0

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().