TRIB2 desensitizes ferroptosis via βTrCP-mediated TFRC ubiquitiantion in liver cancer cells.
TRIB2 desensitizes ferroptosis via βTrCP-mediated TFRC ubiquitiantion in liver cancer cells.
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TRIB2 通过 βTrCP 介导的 TFRC 在肝癌细胞中的泛素化使铁死亡变得不敏感
DOI：
10.1038/s41420-021-00574-1
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发表时间：
2021-07-27
影响因子：
7
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Guo S;Chen Y;Xue X;Yang Y;Wang Y;Qiu S;Cui J;Zhang X;Ma L;Qiao Y;Wang J
Tribbles 同源物 2 (TRIB2) 已知可通过调节泛素 (Ub) 蛋白酶体系统 (UPS) 促进肝脏肿瘤发生。至少涉及两种方式，即充当接头蛋白来调节某些泛素 E3 连接酶 (E3) 的泛素化功能，并通过增加蛋白酶体的蛋白水解活性来降低总体 Ub 水平。最近，我们发现 TRIB2 通过减少 Ub 的可用性来缓解氧化损伤，而 Ub 对于谷胱甘肽过氧化物酶 4 (GPX4) 的泛素化和随后的降解至关重要。尽管 GPX4 是防止铁死亡的关键抗氧化因子，但缺乏表明 TRIB2 使铁死亡脱敏的确切证据。此外，此类功能是否通过 E3 仍不清楚。在这里，我们证明 TRIB2 的缺失通过提高肝癌细胞中的不稳定铁来使铁死亡变得敏感。相比之下，TRIB2 的过度表达会导致相反的结果。我们进一步证明 TRIB2 需要转铁蛋白受体 (TFRC) 才能使细胞对铁死亡不敏感。如果没有 TFRC，不稳定铁池就无法通过过度表达 TRIB2 来减少。我们还发现，含有E3泛素蛋白连接酶（βTrCP）的β转导蛋白重复序列是TFRC泛素化的真正E3，一旦βTrCP被敲除，TRIB2就无法降低不稳定铁水平。此外，我们还证实TRIB2敲除和过表达对铁死亡和铁死亡相关脂质活性氧（ROS）产生的相反影响都是TFRC和βTrCP不可或缺的。最后，我们证明 TRIB2 专门操纵 RSL3 和erastin 诱导的铁死亡，不依赖于 GPX4 和谷胱甘肽 (GSH)。总之，我们阐明了 TRIB2 通过 E3 βTrCP 使铁死亡脱敏的新作用，从而促进 TFRC 泛素化，最终减少肝癌细胞中的不稳定铁。
Tribbles homolog 2 (TRIB2) is known to boost liver tumorigenesis via regulating Ubiquitin (Ub) proteasome system (UPS). At least two ways are involved, i.e., acts as an adaptor protein to modulate ubiquitination functions of certain ubiquitin E3 ligases (E3s) and reduces global Ub levels via increasing the proteolysis activity of proteasome. Recently, we have identified the role of TRIB2 to relieve oxidative damage via reducing the availability of Ub that is essential for the ubiquitination and subsequent degradation of Glutathione peroxidase 4 (GPX4). Although GPX4 is a critical antioxidant factor to protect against ferroptosis, the exact evidence showing that TRIB2 desensitizes ferroptosis is lacking. Also, whether such function is via E3 remains unclear. Here, we demonstrated that deletion of TRIB2 sensitized ferroptosis via lifting labile iron in liver cancer cells. By contrast, overexpression of TRIB2 led to the opposite outcome. We further demonstrated that transferrin receptor (TFRC) was required for TRIB2 to desensitize the cells to ferroptosis. Without TFRC, the labile iron pool could not be reduced by overexpressing TRIB2. We also found that beta-transducin repeat containing E3 ubiqutin protein ligase (βTrCP) was a genuine E3 for the ubiquitination of TFRC, and TRIB2 was unable to decline labile iron level once upon βTrCP was knocked out. In addition, we confirmed that the opposite effects on ferroptosis and ferroptosis-associated lipid reactive oxygen species (ROS) generation resulted from knockout and overexpression of TRIB2 were all indispensible of TFRC and βTrCP. Finally, we demonstrated that TRIB2 exclusively manipulated RSL3- and erastin-induced-ferroptosis independent of GPX4 and glutathione (GSH). In conclusion, we elucidated a novel role of TRIB2 to desensitize ferroptosis via E3 βTrCP, by which facilitates TFRC ubiquitiation and finally decreases labile iron in liver cancer cells.
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影响因子：
14.8
作者：
Kagan VE;Mao G;Qu F;Angeli JP;Doll S;Croix CS;Dar HH;Liu B;Tyurin VA;Ritov VB;Kapralov AA;Amoscato AA;Jiang J;Anthonymuthu T;Mohammadyani D;Yang Q;Proneth B;Klein-Seetharaman J;Watkins S;Bahar I;Greenberger J;Mallampalli RK;Stockwell BR;Tyurina YY;Conrad M;Bayır H
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Stockwell BR
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