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

Omkar Shinde; Joshua A Boyer; Stephanie Cambier; Jordyn J VanPortfliet; Xuewu Sui; Gaya P Yadav; Elizabeth G Viverette; Mario J Borgnia; A Phillip West; Qi Zhang; Daniel B Stetson; Pingwei Li

doi:10.1016/j.immuni.2024.12.002

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

Immunity. 2025 Jan 2:S1074-7613(24)00566-1. doi: 10.1016/j.immuni.2024.12.002. Online ahead of print.

Authors

Affiliations

¹ Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
² Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA; RNA Discovery Center, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
³ Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA.
⁴ The Jackson Laboratory, Bar Harbor, ME 04609, USA.
⁵ Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
⁶ Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA. Electronic address: pingwei@tamu.edu.

PMID: 39765229
DOI: 10.1016/j.immuni.2024.12.002

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.

Published by Elsevier Inc.