美国德州农工大学Pingwei Li研究团队发现，ATP结合盒转运蛋白ABCC1的结构，揭示了环状二核苷酸cGAMP外排的分子基础。这一研究成果于2025年1月6日在线发表在国际学术期刊《免疫》上。

研究人员表示，环状核苷酸GMP-AMP（cGAMP）在通过环状GMP-AMP合成酶（cGAS）-干扰素基因刺激因子（STING）通路，介导先天免疫反应中发挥着关键作用。近期研究表明，ATP结合盒C亚家族成员1（ABCC1）是cGAMP的外排蛋白。外排的cGAMP可以被未感染的细胞摄取，刺激STING介导的先天免疫反应。然而，ABCC1介导的cGAMP外排的分子基础仍不清楚。

研究人员报告了人类ABCC1在无配体状态，和与cGAMP结合状态下的冷冻电子显微镜（cryo-EM）结构。这些结构揭示，ABCC1通过其N端跨膜结构域形成同源二聚体。配体结合的结构表明，cGAMP被一个带正电荷的口袋识别。突变和功能研究确认了，配体结合口袋在cGAMP识别和外排中的作用。

该研究为ABCC1作为cGAMP外排蛋白的结构和功能，提供了深入的见解，并为未来在感染和抗癌免疫中，靶向ABCC1的研究奠定了基础。

附：英文原文

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

Author: 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

Issue&Volume: 2025-01-06

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.

DOI: 10.1016/j.immuni.2024.12.002

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00566-1