SLC19A1 Is an Importer of the Immunotransmitter cGAMP

Mol Cell. 2019 Jul 25;75(2):372-381.e5. doi: 10.1016/j.molcel.2019.05.006. Epub 2019 May 21.

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'-CDAS). These discoveries will provide insight into cGAMP's role as an immunotransmitter and aid in the development of more targeted CDN-based cancer therapeutics.

Keywords: 2′3′-cGAMP; CDN; SLC19A1; STING; cGAMP; cyclic dinucleotide; immune therapy; immunotransmitter.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • CRISPR-Cas Systems / genetics
  • Cell Line, Tumor
  • Cell Membrane / genetics
  • Genome, Human / genetics
  • Humans
  • Immunity, Innate / genetics*
  • Membrane Proteins / genetics
  • Neoplasms / genetics*
  • Neoplasms / immunology
  • Nucleotides, Cyclic / genetics*
  • Nucleotides, Cyclic / immunology
  • Reduced Folate Carrier Protein / genetics*
  • Signal Transduction / genetics

Substances

  • Membrane Proteins
  • Nucleotides, Cyclic
  • Reduced Folate Carrier Protein
  • SLC19A1 protein, human
  • STING protein, human
  • cyclic guanosine monophosphate-adenosine monophosphate