Iron-sulfur cluster deficiency can be sensed by IRP2 and regulates iron homeostasis and sensitivity to ferroptosis independent of IRP1 and FBXL5.
Iron-sulfur cluster deficiency can be sensed by IRP2 and regulates iron homeostasis and sensitivity to ferroptosis independent of IRP1 and FBXL5.
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DOI：
10.1126/sciadv.abg4302
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发表时间：
2021-05
期刊：
影响因子：
13.6
通讯作者：
Possemato R
中科院分区：
文献类型：
--
作者：
Terzi EM;Sviderskiy VO;Alvarez SW;Whiten GC;Possemato R
铁硫簇使细胞能够感觉到它们有适量的铁，并保护它们免受自我毁灭。细胞内铁水平受到严格调节，以支持体内平衡并避免铁介导的ROS产生。铁硫簇（ISC）合成的丧失可增加铁负荷并通过铁凋亡促进细胞死亡。铁反应元件结合蛋白IRP1和IRP2转录后调节铁稳态。IRP1与靶mRNA的结合受ISC占用的竞争性调节。然而，IRP2主要被认为是通过E3泛素连接酶FBXL5介导的降解在蛋白质水平上调节。在这里，我们表明，ISC合成抑制可以激活IRP2和促进铁凋亡的敏感性，通过以前未确定的机制。在组织水平的O2浓度下，ISC缺乏增强了IRP2与靶mRNA的结合，而不依赖于IRP1、FBXL5和IRP2蛋白水平的变化。IRP1和IRP2的缺失废除铁饥饿反应，防止其激活ISC合成抑制。这些发现将为操纵铁凋亡敏感性的策略提供信息，并帮助阐明ISC生物合成障碍（例如弗里德赖希共济失调）的潜在机制。
Iron-sulfur clusters enable cells to sense that they have the right amount of iron, and protect them from self-destruction. Intracellular iron levels are strictly regulated to support homeostasis and avoid iron-mediated ROS production. Loss of iron-sulfur cluster (ISC) synthesis can increase iron loading and promote cell death by ferroptosis. Iron-responsive element-binding proteins IRP1 and IRP2 posttranscriptionally regulate iron homeostasis. IRP1 binding to target mRNAs is competitively regulated by ISC occupancy. However, IRP2 is principally thought to be regulated at the protein level via E3 ubiquitin ligase FBXL5–mediated degradation. Here, we show that ISC synthesis suppression can activate IRP2 and promote ferroptosis sensitivity via a previously unidentified mechanism. At tissue-level O2 concentrations, ISC deficiency enhances IRP2 binding to target mRNAs independent of IRP1, FBXL5, and changes in IRP2 protein level. Deletion of both IRP1 and IRP2 abolishes the iron-starvation response, preventing its activation by ISC synthesis inhibition. These findings will inform strategies to manipulate ferroptosis sensitivity and help illuminate the mechanism underlying ISC biosynthesis disorders, such as Friedreich’s ataxia.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
DOI：
10.1124/jpet.118.252759
发表时间：
2019-04-01
影响因子：
3.5
作者：
Cotticelli, M. Grazia;Xia, Shujuan;Wilson, Robert B.
通讯作者：
Wilson, Robert B.
DOI：
10.1073/pnas.84.23.8478
发表时间：
1987-12-01
影响因子：
11.1
作者：
AZIZ, N;MUNRO, HN
通讯作者：
MUNRO, HN
影响因子：
4.8
作者：
Pietsch, EC;Chan, JY;Torti, SV
通讯作者：
Torti, SV
DOI：
10.1016/j.mcn.2012.08.003
发表时间：
2013-07
期刊：
Molecular and cellular neurosciences
影响因子：
--
作者：
Vaubel RA;Isaya G
通讯作者：
Isaya G