The structure of erastin-bound xCT-4F2hc complex reveals molecular mechanisms underlying erastin-induced ferroptosis
The structure of erastin-bound xCT-4F2hc complex reveals molecular mechanisms underlying erastin-induced ferroptosis
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DOI：
10.1038/s41422-022-00642-w
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Wang Fudi
中科院分区：
文献类型：
--
作者：
Yan Renhong;Xie Enjun;Li Yaning;Li Jin;Zhang Yuanyuan;Chi Ximin;Hu Xueping;Xu Lei;Hou Tingjun;Stockwell Brent R;Min Junxia;Zhou Qiang;Wang Fudi
Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death characterized by an accumulation of lipid-derived reactive oxygen species (ROS). The small-molecule compound erastin induces ferroptosis via inhibiting the cystine-glutamate antiporter system x_c~-, which consists of two subunits, namely the light chain xCT and the heavy chain 4F2hc (encoded by the SLC7A11 and SLC3A2 genes, respectively). Recent studies have shown that xCT (SLC7A11) regulates ferroptosis in liver fibrosis, cardiomyopathy, and numerous other pathophysiological processes. The complex formed by xCT and 4F2hc has also been suggested as a possible therapeutic target for cancer, as it is overexpressed in a wide variety of cancer types; moreover, inhibiting xCT impairs cystine uptake, causing an accumulation of ROS and suppressing tumor growth.9,10 However, the underlying molecular mechanisms remain unknown. Here, we overexpressed and then co-purified human xCT and 4F2hc, finding that they form a stable complex (Fig. 1a). To test whether this purified complex is functional, we then reconstituted the complex into liposomes and performed a counter-flow assay. We found that the wild-type (WT) xCT-4F2hc complex mediates the exchange of cystine and glutamate-measured as the uptake of ~(14)C-labeled cystine-and this activity was significantly reduced by the system xc-inhibitors, erastin and sulfasalazine (Supplementary information, Fig. S1).
