SLC19A1 Is an Importer of the Immunotransmitter cGAMP.

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.

journal_name

Mol Cell

journal_title

Molecular cell

authors

Ritchie C,Cordova AF,Hess GT,Bassik MC,Li L

doi

10.1016/j.molcel.2019.05.006

subject

Has Abstract

pub_date

2019-07-25 00:00:00

pages

372-381.e5

issue

2

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(19)30359-4

journal_volume

75

pub_type

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