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. 2025 Jan 14;58(1):59-73.e5.
doi: 10.1016/j.immuni.2024.12.002. Epub 2025 Jan 6.

Structures of ATP-binding cassette transporter ABCC1 reveal the molecular basis of cyclic dinucleotide cGAMP export

Omkar Shinde  1 , Joshua A Boyer  2 , Stephanie Cambier  3 , Jordyn J VanPortfliet  4 , Xuewu Sui  1 , Gaya P Yadav  1 , Elizabeth G Viverette  5 , Mario J Borgnia  5 , A Phillip West  4 , Qi Zhang  2 , Daniel B Stetson  3 , Pingwei Li  6
Affiliations

Structures of ATP-binding cassette transporter ABCC1 reveal the molecular basis of cyclic dinucleotide cGAMP export

Omkar Shinde et al. Immunity. .

Abstract

Cyclic nucleotide GMP-AMP (cGAMP) plays a critical role in mediating the innate immune response through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Recent studies showed that ATP-binding cassette subfamily C member 1 (ABCC1) is a cGAMP exporter. The exported cGAMP can be imported into uninfected cells to stimulate a STING-mediated innate immune response. However, the molecular basis of cGAMP export mediated by ABCC1 remains unclear. Here, we report the cryoelectron microscopy (cryo-EM) structures of human ABCC1 in a ligand-free state and a cGAMP-bound state. These structures reveal that ABCC1 forms a homodimer via its N-terminal transmembrane domain. The ligand-bound structure shows that cGAMP is recognized by a positively charged pocket. Mutagenesis and functional studies confirmed the roles of the ligand-binding pocket in cGAMP recognition and export. This study provides insights into the structure and function of ABCC1 as a cGAMP exporter and lays a foundation for future research targeting ABCC1 in infection and anti-cancer immunity.

Keywords: ABCC1/MRP1; cGAMP export; cGAS-STING pathway; innate immunity.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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