Regulation of Anion Channel LRRC8 Volume-Regulated Anion Channels in Transport of 2′3′-Cyclic GMP–AMP and Cisplatin under Steady State and Inflammation

作者：Xia Chen, Li Wang, Limin Cao, Tiantian Li, Zhihong Li, Yumeng Sun, Jinqiu Ding, Chun Zhou, Yadong Xie, Nan Yue, Nan Jing, Xin‐Ming Jia, Chao Peng, Huabin Li, Jinbo Yang, Hui Xiao · 发表于：The Journal of Immunology · 年份：2021 · DOI：10.4049/jimmunol.2000989 · 被引用次数：25 · 研究领域：interferon and immune responses、Mosquito-borne diseases and control、RNA regulation and disease

The recently identified anion channel LRRC8 volume-regulated anion channels (VRACs) are heteromeric hexamers constituted with the obligate LRRC8A subunit paired with at least one of the accessory LRRC8B to LRRC8E subunits. In addition to transport chloride, taurine, and glutamate, LRRC8 VRACs also transport the anticancer agent cisplatin and STING agonists 2'3'-cyclic GMP-AMP (cGAMP) and cyclic dinucleotides; hence, they are implicated in a variety of physiological and pathological processes, such as cell swelling, stroke, cancer, and viral infection. Although the subunit composition largely determines VRAC substrate specificity, the opening of various VRAC pores under physiological and pathological settings remains enigmatic. In this study, we demonstrated that VRACs comprising LRRC8A and LRRC8E (LRRC8A/E-containing VRACs), specialized in cGAMP transport, can be opened by a protein component present in serum under resting condition. Serum depletion ablated the tonic activity of LRRC8A/E-containing VRACs, decreasing cGAMP transport in various human and murine cells. Also, heating or proteinase K treatment abolished the ability of serum to activate VRAC. Genetic analyses revealed a crucial role for cGAMP synthase (cGAS) in serum/TNF-promoted VRAC activation. Notably, the presence of cGAS on the plasma membrane, rather than its DNA-binding or enzymatic activity, enabled VRAC activation. Moreover, phospholipid PIP2 seemed to be instrumental in the membrane localization of cGAS a...