Inhibition of IGF2BP1 attenuates renal injury and inflammation by alleviating m6A modifications and E2F1/MIF pathway.
Inhibition of IGF2BP1 attenuates renal injury and inflammation by alleviating m6A modifications and E2F1/MIF pathway.
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DOI：
10.7150/ijbs.78348
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发表时间：
2023
影响因子：
9.2
通讯作者：
Zhou GP
中科院分区：
文献类型：
--
作者：
Mao Y;Jiang F;Xu XJ;Zhou LB;Jin R;Zhuang LL;Juan CX;Zhou GP
脓毒性急性肾损伤（阿基）的特征是炎症。焦亡通常发生在阿基期间，并与脓毒性阿基的发展相关。本研究发现，诱导胰岛素样生长因子2 mRNA结合蛋白1（IGF 2BP 1）达到较高水平可诱导肾小管细胞的焦亡。同时，巨噬细胞移动抑制因子（MIF），NLRP 3炎性小体的亚基，是IGF 2BP 1诱导的焦亡所必需的。通过生物信息学分析，在E2 F转录因子1（E2 F1）mRNA的3′-UTR区域发现了一个m6 A识别位点，并通过突变和荧光素酶实验进行了验证。进一步的放线菌素D（Act D）追踪实验表明，IGF 2BP 1稳定E2 F1 mRNA依赖于m6 A。电泳迁移率变动分析（EMSA）和染色质免疫沉淀（ChIP）表明E2 F1作为转录因子促进MIF的表达。因此，IGF 2BP 1通过m6 A修饰直接上调E2 F1表达而上调MIF。对盲肠结扎穿孔（CLP）手术小鼠的实验验证了IGF 2BP 1、E2 F1和MIF之间的关系，并证明了IGF 2BP 1在体内MIF相关的焦亡中的意义。总之，IGF 2BP 1通过靶向NLRP 3炎性体的MIF组分，在脓毒性阿基中是有效的焦亡诱导剂。抑制IGF 2BP 1可能是脓毒性阿基的一种替代性基于脓毒性的治疗方法。
Septic acute kidney injury (AKI) is characterized by inflammation. Pyroptosis often occurs during AKI and is associated with the development of septic AKI. This study found that induction of insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) to a higher level can induce pyroptosis in renal tubular cells. Meanwhile, macrophage migration inhibitory factor (MIF), a subunit of NLRP3 inflammasomes, was essential for IGF2BP1-induced pyroptosis. A putative m6A recognition site was identified at the 3′-UTR region of E2F transcription factor 1 (E2F1) mRNA via bioinformatics analyses and validated using mutation and luciferase experiments. Further actinomycin D (Act D) chase experiments showed that IGF2BP1 stabilized E2F1 mRNA dependent on m6A. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) indicated that E2F1 acted as a transcription factor to promote MIF expression. Thus, IGF2BP1 upregulated MIF through directly upregulating E2F1 expression via m6A modification. Experiments on mice with cecum ligation puncture (CLP) surgery verified the relationships between IGF2BP1, E2F1, and MIF and demonstrated the significance of IGF2BP1 in MIF-associated pyroptosis in vivo. In conclusion, IGF2BP1 was a potent pyroptosis inducer in septic AKI through targeting the MIF component of NLRP3 inflammasomes. Inhibiting IGF2BP1 could be an alternate pyroptosis-based treatment for septic AKI.
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影响因子：
7.4
作者：
Geng J;Qiu Y;Qin Z;Su B
通讯作者：
Su B
影响因子：
10.5
作者：
BERNSTEIN, PL;HERRICK, DJ;ROSS, J
通讯作者：
ROSS, J
影响因子：
4.4
作者：
Faherty N;O'Donovan H;Kavanagh D;Madden S;McKay GJ;Maxwell AP;Martin F;Godson C;Crean J
通讯作者：
Crean J
影响因子：
12.4
作者：
Jiang, Ling;Liu, Xueqi;Hu, Xueru;Gao, Li;Zeng, Hanxu;Wang, Xian;Huang, Yuebo;Zhu, Wei;Wang, Jianan;Wen, Jiagen;Meng, Xiaoming;Wu, Yonggui
通讯作者：
Wu, Yonggui
影响因子：
5.6
作者：
Li, Man;Yu, Jia;Wang, Wei-xing
通讯作者：
Wang, Wei-xing