更新于：2024-05-01

EIF4E2

eukaryotic translation initiation factor 4E family member 2

更新于：2024-05-01

基本信息

别名

4EHP、eIF-4E type 2、eIF4E type 2

+ [11]

简介

Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation. Acts as a repressor of translation initiation (PubMed:17368478, PubMed:22751931, PubMed:25624349, PubMed:33581076, PubMed:9582349). In contrast to EIF4E, it is unable to bind eIF4G (EIF4G1, EIF4G2 or EIF4G3), suggesting that it acts by competing with EIF4E and block assembly of eIF4F at the cap (By similarity). In P-bodies, component of a complex that promotes miRNA-mediated translational repression (PubMed:28487484). Involved in virus-induced host response by mediating miRNA MIR34A-induced translational silencing which controls IFNB1 production by a negative feedback mechanism (PubMed:28487484, PubMed:33581076). Component of the 4EHP-GYF2 complex, a multiprotein complex that acts as a repressor of translation initiation (PubMed:22751931, PubMed:35878012). In association with GIGYF2, assists ribosome-associated quality control (RQC) by sequestering the mRNA cap, blocking ribosome initiation and decreasing the translational load on problematic messages. Part of a pathway that works in parallel to RQC-mediated degradation of the stalled nascent polypeptide. GIGYF2 and EIF4E2 work downstream and independently of ZNF598, which seems to work as a scaffold that can recruit them to faulty mRNA even if alternative recruitment mechanisms may exist (PubMed:32726578). (Microbial infection) Upon SARS coronavirus-2/SARS-CoV-2 infection, the interaction with non-structural protein 2 (nsp2) with GIGYF2 enhances GIGYF2 binding to EIF4E2 and increases repression of translation initiation of genes involved in antiviral innate immune response such as IFNB1.

关联

100 项与 EIF4E2 相关的临床结果

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100 项与 EIF4E2 相关的转化医学

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0 项与 EIF4E2 相关的专利（医药）

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136

项与 EIF4E2 相关的文献（医药）

2023-10-06·Nature communications

Systematic functional interrogation of SARS-CoV-2 host factors using Perturb-seq

Article

作者: Sunshine, Sara ; Puschnik, Andreas S. ; Replogle, Joseph M. ; Laurie, Matthew T. ; Liu, Jamin ; Zha, Beth Shoshana ; Nunez, James K. ; Byrum, Janie R. ; McMorrow, Aidan H. ; Frieman, Matthew B. ; Winkler, Juliane ; Qiu, Xiaojie ; Rosenberg, Oren S. ; Leonetti, Manuel D. ; Ye, Chun Jimmie ; Weissman, Jonathan S. ; DeRisi, Joseph L. ; Hein, Marco Y.

Genomic and proteomic screens have identified numerous host factors of SARS-CoV-2, but efficient delineation of their molecular roles during infection remains a challenge. Here we use Perturb-seq, combining genetic perturbations with a single-cell readout, to investigate how inactivation of host factors changes the course of SARS-CoV-2 infection and the host response in human lung epithelial cells. Our high-dimensional data resolve complex phenotypes such as shifts in the stages of infection and modulations of the interferon response. However, only a small percentage of host factors showed such phenotypes upon perturbation. We further identified the NF-κB inhibitor IκBα (NFKBIA), as well as the translation factors EIF4E2 and EIF4H as strong host dependency factors acting early in infection. Overall, our study provides massively parallel functional characterization of host factors of SARS-CoV-2 and quantitatively defines their roles both in virus-infected and bystander cells.

2023-10-06·Cell death & disease

α1,3-fucosylation of MEST promotes invasion potential of cytotrophoblast cells by activating translation initiation.

Article

作者: Hao Wang ; Xinyuan Cui ; Luyao Wang ; Ningning Fan ; Ming Yu ; Huamin Qin ; Shuai Liu ; Qiu Yan

Embryo implantation into the uterus is the gateway for successful pregnancy. Proper migration and invasion of embryonic trophoblast cells are the key for embryo implantation, and dysfunction causes pregnancy failure. Protein glycosylation plays crucial roles in reproduction. However, it remains unclear whether the glycosylation of trophoblasts is involved in trophoblast migration and invasion processes during embryo implantation failure. By Lectin array, we discovered the decreased α1,3-fucosylation, especially difucosylated Lewis Y (LeY) glycan, in the villus tissues of miscarriage patients when compared with normal pregnancy women. Downregulating LeY biosynthesis by silencing the key enzyme fucosyltransferase IV (FUT4) inhibited migration and invasion ability of trophoblast cells. Using proteomics and translatomics, the specific LeY scaffolding glycoprotein of mesoderm-specific transcript (MEST) with glycosylation site at Asn163 was identified, and its expression enhanced migration and invasion ability of trophoblast cells. The results also provided novel evidence showing that decreased LeY modification on MEST hampered the binding of MEST with translation factor eIF4E2, and inhibited implantation-related gene translation initiation, which caused pregnancy failure. The α1,3-fucosylation of MEST by FUT4 may serve as a new biomarker for evaluating the functional state of pregnancy, and a target for infertility treatment.

2023-10-01·International journal of radiation oncology, biology, physics

The Effect of PARP Inhibitor Radiosensitization on the mRNA Translational Regulation of T Cell Chemokines.

Article

作者: X Ran ; X Zhang ; M Teng ; W B Alawi ; S Nahum ; H He ; B H Lok

PURPOSE/OBJECTIVE(S):

Immunotherapy has modestly improved survival for small cell lung cancer (SCLC) patients. Low response rate and rapid disease progression remain an intractable challenge. One of the factors that contribute to immunotherapy resistance is the lack of cytotoxic T cell infiltration. The expression of chemoattractant cytokines, like CCL5 and CXCL10, are essential for T cell infiltration. The control of chemokine expression is not fully understood, but both transcriptional and translational control pathways could play a major role. Previous studies have shown a correlation between DNA damage and chemokine expression and that PARP inhibitors (PARPi) are radiosensitizers for SCLC that increases DNA damage. The objectives of this study were to define this potential PARPi immunogenic radiosensitizing relationship.

MATERIALS/METHODS:

We identified doses of olaparib+ radiation treatment (RT) that conferred radiosensitization in SCLC cell-lines by cell viability and/or clonogenic assays. Olaparib+RT induced CCL5 and CXCL10 mRNA expression was measured by qPCR across SCLC cell-lines. Protein level of chemokines was assessed by immunoblotting. SBC5 cells were treated with olaparib+RT and submitted for RNA sequencing analysis. Genes with adjusted p value<0.05 were considered significant. Protein level changes and target gene knock-out (KO) were confirmed by immunoblotting. Chemokine CXCL10 mRNA and protein level in wildtype (WT) and KO cells were measured by qPCR and western blot, respectively. A mRNA decay assay and dual-luciferase reporter assay was used to identify the region of CXCL10 mRNA that confers mRNA stability control. In vivo anti-tumor efficacy and tumor T cell infiltration studies were done in B6129F mice bearing KP1 tumors. And the T cell infiltration was measured by immune profiling.

RESULTS:

In vitro, olaparib+RT significantly increased CXCL10 mRNA in all four SCLC subtype cell-lines in comparison to vehicle control. Consistently, the increase of CXCL10 protein levels (3-fold) was observed in SBC5 cells. By RNA-Seq, a top-ranking translational repressor was EIF4E2 (4EHP) mRNA. The downregulation of EIF4E2 protein by olaparib+RT was validated in four SCLC subtypes by western blot. EIF4E2 KO in HEK293 and SBC5 cells increased CXCL10 mRNA and protein level. By mRNA decay assay and western blot, the absence of EIF4E2 stabilized CXCL10 mRNA and increased CXCL10 protein levels. The dual-luciferase assay demonstrated EIF4E2 destabilizes CXCL10 mRNA via the 3'UTR of CXCL10. In vivo, immune profiling showed olaparib+RT significantly increased the total T cell and CD8+ T cell infiltration. Finally, anti-PD-L1 inhibition potentiated olaparib + IR to improve tumor control in KP1 allograft.

CONCLUSION:

Our study demonstrated olaparib + RT increases CXCL10 protein levels through downregulating EIF4E2 to subsequently increase T cell infiltration. Olaparib + RT enhanced anti-PD-L1 immunotherapy efficacy and has therapeutic potential as an immunogenic radiosensitizer.

1

项与 EIF4E2 相关的新闻（医药）

2022-08-01

·中国生物技术网

Cell：董欣年团队揭示蛋白翻译重编程新机制

北京时间2022年7月30日，在发表于Cell杂志的一项研究中，美国杜克大学董欣年（Xinnian Dong）团队揭示了分子模式激活的免疫反应（PTI）信号通路中一个全新的蛋白翻译起始模块（Module）——PABP/R-motif介导的非帽结构依赖的胁迫相关蛋白的翻译。这一发现为真核生物蛋白翻译重编程提供了不同于经典的eIF2a磷酸化通路的理论模型，对研究其他真核生物蛋白重编程具有普遍的借鉴意义。真核生物的mRNA翻译起始（Translation initiation）是一个极其复杂的过程。在没有胁迫的条件下，绝大多数真核mRNA的翻译起始依赖于其位于5’端的m7G帽结构（Cap structure）。为了起始翻译，eIF2-GTP-Met-tRNAi三聚体与40S核糖体亚基进行组装形成43S前起始复合物（43S preinitiation complex, PIC），其中eIF2包含三个蛋白eIF2α、eIF2β和eIF2γ。43S PIC随后被eIF4F起始复合体招募到位于mRNA 5’端的m7G帽子结构启动对mRNA从5’端到3’端的扫描，直至遇到合适的起始密码子，其中eIF4F复合体包括 m7G帽结构结合蛋白eIF4E、支架蛋白eIF4G和解旋酶eIF4A。起始密码子的识别会招募60S核糖体亚基，形成80S起始复合体开始蛋白的合成。值得注意的是，与3’端poly(A)结合的PABP（Poly(A)-binding protein）可以促进43S PIC的招募过程。在遭遇胁迫时，真核生物通常通过eIF2α磷酸化抑制经典的m7G帽结构依赖的翻译，同时选择性地翻译胁迫必须的调节蛋白（Stress regulators），从而实现体内蛋白翻译的重编程（Reprogramming）。然而，在植物的PTI信号通路中，通过敲除GCN2完全阻断eIF2α磷酸化并没有发现其对翻译重编程的显著影响，暗示了在植物的PTI信号通路中存在全新的蛋白翻译重编程机制。植物PTI信号通路中蛋白翻译重编程模式图王金龙等的研究发现，病原菌侵染可以促进DCP蛋白（Decapping protein）去除mRNA 5’端的m7G帽结构来抑制经典的帽结构依赖的蛋白翻译（Cap-dependent translation），而在5’端先导序列（Leader sequence）含有R-motif（Purine-rich element）的抗病相关mRNA，则可以利用R-motif作为m7G帽结构的代替者（Cap surrogate）——一个新式的胞内IRES（Internal ribosome entry site），结合PABP蛋白来选择性地启动自身的翻译。在正常生长条件下，不含有R-motif的生长相关的mRNA通过m7G帽结构依赖的方式进行翻译。当PTI信号被激活后，PABP会选择性地结合激活后的eIFiso4G（eIF4G异构体）促进含有R-motif的抗病相关mRNA的翻译。值得注意的是，从经典的m7G帽结构依赖的蛋白翻译到R-motif介导的非帽结构依赖蛋白翻译的转变，是通过PTI信号通路中的关键激酶MPK3/6 来实现的。当PTI信号被接受后，MPK3/6会被激活，诱导mRNA去除5’端的帽子结构，并磷酸化eIF4G来抑制生长相关mRNA的翻译；同时磷酸化PABP增强其与R-motif之间的结合，激活eIFiso4G蛋白，促进含有R-motif的抗病相关mRNA的翻译。本研究揭示了不同于经典的eIF2α磷酸化介导的蛋白重编程机制，同时因为R-motif同样广泛存在于果蝇、小鼠和人体的胁迫相关mRNA的5’端前导序列中，本研究发现的蛋白翻译起始调控机制可能同样广泛存在于其他真核生物体中。相关论文信息：https://doi-org.libproxy1.nus.edu.sg/10.1016/j.cell.2022.06.037

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