SLC19A1 Transports STING-Stimulating Cyclic Dinucleotides into Cells

The presence of the cyclic dinucleotide (CDN) 2′3′-cGAMP in the cytosol activates stimulator of interferon genes (STING), triggering a signaling cascade that culminates in an immune response. 2′3′-cGAMP is produced by cancer cells, and synthetic CDNs are used in cancer immunotherapy, but the mechanism by which these charged molecules are transported across cell membranes and into target cells is unclear. Using a genome-wide CRISPR-interference forward-genetic screen, Luteijn, Zaver, and colleagues identified the reduced-folate carrier SLC19A1 as the predominant transporter of CDNs in human cells. Validating this finding, SLC19A1-deficient cells exhibited reduced responses to stimulation by CDNs and reduced 2′3′-cGAMP uptake, whereas overexpression of SLC19A1 led to a heightened response to CDNs and an increase in 2′3′-cGAMP uptake. In SLC19A1-depleted cells, STING function was restored upon direct introduction of CDNs into the cytosol, indicating that the role of SLC19A1 in this pathway is, indeed, to transport CDNs across the cell membrane. Experiments with other CDNs revealed that SLC19A1′s transporter function is not specific to the phosphodiester linkage or base content of the CDN; thus, SLC19A1 appears to be a general CDN transporter. Pulldown experiments using His-tagged SLC19A1 supported a direct interaction between SLC19A1 and 2′3′-cGAMP, as would be predicted if SLC19A1 is a CDN transporter. Notably, the effects of CDN stimulation were not completely abolished in SLC19A1-null cells, implying that human cells possess another transporter capable, at least to some degree, of ferrying CDNs across the cell membrane. Collectively, these results establish the role of SLC19A1 in the STING pathway and suggest that SLC19A1 may be of interest in investigations of mechanisms behind cancer immunotherapy and immunopathology.

Luteijn RD, Zaver SA, Gowen BG, Wyman SK, Garelis NE, Onia L, et al. SLC19A1 transports immunoreactive cyclic dinucleotides. Nature 2019;573:434–8.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.