Genome-wide screen for host factors involved in STING activation |New Voices in Infection Biology

  • Datum: 28.10.2020
  • Uhrzeit: 16:00
  • Vortragende(r): Rutger Luteijn
  • University of California, Berkeley, USA
  • Ort: Zoom video conference
  • Gastgeber: Olivia Majer
  • Kontakt:
Genome-wide screen for host factors involved in STING activation |New Voices in Infection Biology

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Talk abstract:

The accumulation of DNA in the cytosol serves as a key immunostimulatory signal associated with infections, cancer and genomic damage. Cytosolic DNA triggers immune responses by activating the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway. The binding of DNA to cGAS leads to the synthesis of a second messenger, cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP). This cyclic dinucleotide (CDN), activates STING, which promotes the transcription of factors that stimulate a broader immune response. Exogenous 2′3′-cGAMP produced by malignant cells and other CDNs, including those produced by bacteria and synthetic CDNs used in cancer immunotherapy, 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 host factors involved in activation by extracellular CDNs. We found the reduced folate carrier SLC19A1 as the major transporter of CDNs in human cells. CDN uptake is inhibited by previously identified SLC19A1 substrates, including folates and two medications approved for treatment of inflammatory diseases, sulfasalazine and the antifolate methotrexate. In addition to SLC19A1, our screen revealed many other host factors that regulate STING activation by CDNs. The role of SLC19A1 and other newly-identified factors affecting the STING immune response has implications for the immunotherapeutic treatment of cancer, host responsiveness to CDN-producing pathogenic microorganisms and, potentially, for certain inflammatory diseases.

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