Structure-based mechanisms of 2'3'-cGAMP intercellular transport in the cGAS-STING immune pathway.

Dinshaw J Patel, Wei Xie

Journal: Trends in immunology 2023;44(6):450-467

PMID: 37147228

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Abstract

Upon activation by double-stranded DNA (dsDNA), the cytosolic dsDNA sensor cyclic GMP-AMP synthase (cGAS) synthesizes the diffusible cyclic dinucleotide 2'3'-cGAMP (cyclic GMP-AMP), which subsequently binds to the adaptor STING, triggering a cascade of events leading to an inflammatory response. Recent studies have highlighted the role of 2'3'-cGAMP as an 'immunotransmitter' between cells, a process facilitated by gap junctions as well as by specialized membrane-spanning importer and exporter channels. This review highlights recent advances from a structural perspective of intercellular trafficking of 2'3'-cGAMP, with particular emphasis on the binding of importer SLC19A1 to 2'3'-cGAMP, as well as the significance of associated folate nutrients and antifolate therapeutics. This provides a path forward for structure-guided understanding of the transport cycle in immunology, as well as for candidate targeting approaches towards therapeutic intervention in inflammation.

Address: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 311027, China; Department of Infectious Diseases, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China. Electronic address: [email protected].; Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Electronic address: [email protected].

DOI: 10.1016/j.it.2023.04.006