预约演示

更新于：2025-05-07

SEH1L

更新于：2025-05-07

基本信息

别名

GATOR complex protein SEH1、Nucleoporin SEH1、Nup107-160 subcomplex subunit SEH1

+ [7]

简介

Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex is required for the assembly of a functional NPC (PubMed:15146057, PubMed:17363900). The Nup107-160 subcomplex is also required for normal kinetochore microtubule attachment, mitotic progression and chromosome segregation. This subunit plays a role in recruitment of the Nup107-160 subcomplex to the kinetochore (PubMed:15146057, PubMed:17363900). As a component of the GATOR2 complex, functions as an activator of the amino acid-sensing branch of the mTORC1 signaling pathway (PubMed:23723238, PubMed:25457612, PubMed:27487210, PubMed:35831510, PubMed:36528027). The GATOR2 complex indirectly activates mTORC1 through the inhibition of the GATOR1 subcomplex (PubMed:23723238, PubMed:27487210, PubMed:35831510, PubMed:36528027). GATOR2 probably acts as an E3 ubiquitin-protein ligase toward GATOR1 (PubMed:36528027). In the presence of abundant amino acids, the GATOR2 complex mediates ubiquitination of the NPRL2 core component of the GATOR1 complex, leading to GATOR1 inactivation (PubMed:36528027). In the absence of amino acids, GATOR2 is inhibited, activating the GATOR1 complex (PubMed:25457612, PubMed:26972053, PubMed:27487210). Within the GATOR2 complex, SEC13 and SEH1L are required to stabilize the complex (PubMed:35831510).

关联

靶点

HDAC6 x SEH1L

作用机制

HDAC6抑制剂 [+1]

在研机构

沈阳药科大学

原研机构

沈阳药科大学

在研适应症

疼痛

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

GSK2188931B

靶点

SEH1L

作用机制

SEH1L inhibitors

在研机构-

原研机构

GSK Plc

在研适应症-

非在研适应症

心肌梗塞

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 SEH1L 相关的临床结果

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100 项与 SEH1L 相关的转化医学

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0 项与 SEH1L 相关的专利（医药）

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项与 SEH1L 相关的文献（医药）

2025-05-01·Pediatric Nephrology

Genetic and clinical spectrum of steroid-resistant nephrotic syndrome with nuclear pore gene mutation

Article

作者: Liao, Panli ; Wang, Xiaowen ; Shao, Wenjun ; Wang, Chun ; Yan, Yuan ; Yang, Huihui ; Zhu, Gaohong

BACKGROUNDSteroid-resistant nephrotic syndrome (SRNS) is insensitive to steroid therapy and overwhelmingly progresses to kidney failure (KF), the known pathogenic genes of which include key subunits of the nuclear pore complex (NPC), a less-recognized contributor to glomerular podocyte injury.METHODSAfter analyzing their clinical characterizations and obtaining parental consent, whole-exome sequencing (WES) was performed on patients with SRNS. Several nucleoporin (NUP) biallelic pathogenic variants were identified and further analyzed by cDNA-PCR sequencing from white cells of peripheral blood, minigene assay, immunohistochemical (IHC) staining, and electron microscopy (EM) ultrastructure observation of kidney biopsy, as well as multiple in silico prediction tools, including 3D protein modeling.RESULTSHere, in six families with SRNS, we identified pathogenic mutations in NUP85/93/107/160 genes. Specifically, the patient with NUP93 mutation developed KF six months after diagnosis at 1 year 2 months. Two missense mutations, c.1655A > G and c.1604A > C, disrupted the protein stability of NUP93 by IHC staining of kidney biopsy. Ultrastructurally, the above mutations led to severe vacuolization and deformed nucleus in podocytes, torn and dissolved glomerular basement membrane, and diffuse foot process effacement. The patient with NUP85 mutation reached chronic kidney disease (CKD) stage 3 after 4 years follow-up, with exons 2-5 in-frame loss and a missense variant at c.511C > T, not affecting NUP85 expression but possibly weakened interaction with Seh1. Additionally, an extended endoplasmic reticulum (ER) tubule was readily observed under EM. Meanwhile, dilated ER was also found in two children with NUP160 mutations (c.3330 delA and c.2407 G > A; c.2241 + 1 (IVS17) G > T and c.3656 T > G), one of which has undergone kidney transplantation. Compound heterozygous variants in NUP107, c.1695 G > C and c.1360 C > T, were found in a 14-year-old girl initially diagnosed with CKD stage 5, with the former variant causing exon 19 skipping and early translation termination. c.1311 + 1(IVS15) G > A and c.1790 C > T were identified in the second affected girl, with the former causing exon 15 skipping and an in-frame loss of aa417-438, which disrupted the stability of NUP107 and interaction with NUP133.CONCLUSIONSOur findings expand the spectrum of phenotypes and genotypes of NUPs-associated SRNS and suggest its possible pathogenic mechanism in nuclear and ER homeostasis.

2024-10-01·Apoptosis

SEH1L siliencing induces ferroptosis and suppresses hepatocellular carcinoma progression via ATF3/HMOX1/GPX4 axis

Article

作者: Sun, Haojia ; Feng, Ziyang ; Cao, Ke ; Liu, Xuewen

AbstractSEH1 like nucleoporin (SEH1L) is an important component of nuclear pore complex (NPC), which is crucial in the regulation of cell division. However, the interrelation between SEH1L expression and tumor progression is less studied. In this research, we performed a systematic bioinformatic analysis about SEH1L using TCGA, Timer 2.0, Cbioportal, UCLAN and CellMiner™ databases in pan-cancer. Besides, we further validated the bioinformatic results through in vitro and in vivo experiments in HCC, including transcriptome sequencing, real-time quantitative PCR (RT-qPCR), western blotting (WB), immunohistochemistry (IHC), cell proliferation assays, clone formation, EdU, transwell, flow cytometry and subcutaneous tumor model. Our results suggested that SEH1L was significantly up-regulated and related to poor prognosis in most cancers, and may serve as a potential biomarker. SEH1L could promote HCC progression in vitro and in vivo. Besides, the next generation sequencing suggested that 684 genes was significantly up-regulated and 678 genes was down-regulated after the knock down of SEH1L. SEH1L siliencing could activate ATF3/HMOX1/GPX4 axis, decrease mitochondrial membrane potential and GSH, but increase ROS and MDA, and these effects could be reversed by the knock down of ATF3. This study indicated that SEH1L siliencing could induce ferroptosis and suppresses hepatocellular carcinoma (HCC) progression via ATF3/HMOX1/GPX4 axis.

2024-03-29·Bioscience Reports

New insights into GATOR2-dependent interactions and its conformational changes in amino acid sensing

Article

作者: Wu, Geng ; Sun, Xuan ; Yang, Can

AbstractEukaryotic cells coordinate growth under different environmental conditions via mechanistic target of rapamycin complex 1 (mTORC1). In the amino-acid-sensing signalling pathway, the GATOR2 complex, containing five evolutionarily conserved subunits (WDR59, Mios, WDR24, Seh1L and Sec13), is required to regulate mTORC1 activity by interacting with upstream CASTOR1 (arginine sensor) and Sestrin2 (leucine sensor and downstream GATOR1 complex). GATOR2 complex utilizes β-propellers to engage with CASTOR1, Sestrin2 and GATOR1, removal of these β-propellers results in substantial loss of mTORC1 capacity. However, structural information regarding the interface between amino acid sensors and GATOR2 remains elusive. With the recent progress of the AI-based tool AlphaFold2 (AF2) for protein structure prediction, structural models were predicted for Sentrin2-WDR24-Seh1L and CASTOR1-Mios β-propeller. Furthermore, the effectiveness of relevant residues within the interface was examined using biochemical experiments combined with molecular dynamics (MD) simulations. Notably, fluorescence resonance energy transfer (FRET) analysis detected the structural transition of GATOR2 in response to amino acid signals, and the deletion of Mios β-propeller severely impeded that change at distinct arginine levels. These findings provide structural perspectives on the association between GATOR2 and amino acid sensors and can facilitate future research on structure determination and function.

项与 SEH1L 相关的新闻（医药）

2024-01-27

·生物探索

Dev Cell | 厦门大学张亮团队发现核孔蛋白Seh1通过抑制神经干细胞中p21转录控制新皮层发育

引言核孔蛋白(Nups)的突变或失调与神经发育性疾病密切相关，但其潜在机制尚不清楚。2024年1月24日，厦门大学张亮团队在Developmental Cell (IF 11.8)在线发表题为“Nucleoporin Seh1 controls murine neocortical development via transcriptional repression of p21 in neural stem cells”的研究论文，该研究表明核孔蛋白Seh1通过抑制神经干细胞中p21的转录来控制小鼠新皮层的发育。该研究发现放射状胶质祖细胞中Nup Seh1的缺失导致神经祖细胞增殖和分化缺陷，最终表现为神经发生受损和小头畸形。干细胞增殖的丧失与核细胞质运输的缺陷无关。相反，转录组分析表明，神经干细胞中Seh1的消融降低了p21的表达，p21的敲低部分恢复了自我更新能力。在机制上，Seh1与核外周的NuRD转录抑制复合物合作调节p21的表达。总之，这些发现确定了Nups通过发挥染色质相关作用和影响神经干细胞增殖来调节大脑发育。核孔蛋白(Nup)的失调已在许多神经发育性疾病中被发现。同时，Nups的消耗导致神经发生受损。Nup153对成体神经干细胞(NSCs)的维持是不可缺少的Nup133缺陷小鼠胚胎沿神经谱系分化效率低下然而，这些发现主要是基于纯合子胚胎发育或敲低方法的分析。在小鼠模型中组织特异性耗竭的证据仍然缺乏。常染色体隐性遗传先天性小头症的一种综合征形式最近被定位于染色体18p11.22-q12.3, Nup sel1位于该区域。前期的研究表明，Seh1在少突胶质细胞分化中起着重要作用。Seh1是否以及如何影响神经发育仍然是一个谜。最初，Nups被认为是核孔复合物(NPCs)的组成部分，它介导核和细胞质间的大分子运输然而，最近的研究表明，Nups与基因组相互作用以控制转录程序。越来越多的证据表明，Nups在细胞类型特异性基因调控中起着关键作用。Nup153与Sox2相互作用，调控成人NSCs的转录程序。之前的研究也发现，Seh1募集Olig2和Brd7组装转录激活复合物，促进少突胶质细胞分化Nups如何参与基因激活或基因沉默过程的分子细节似乎取决于Nups的结合伙伴。组蛋白修饰因子和染色质重塑因子参与了Nups介导的转录调控核小体重塑和去乙酰化(NuRD)复合体控制着基因的编程发育过程中的细胞状态，包括胚胎干细胞和祖细胞的分化。然而，在大脑发育过程中，NuRD复合物在细胞状态编程中的作用仍然知之甚少。模式图（Credit: Developmental Cell）该研究发现Seh1是通过与NuRD复合物合作来维持NSC增殖和正常神经发生所必需的。重要的是，Seh1的这个功能与NuRD组件的导入没有关联。相反，Seh1可以将NuRD募集到p21并维持p21处于抑制状态。总之，该研究确定了Seh1在NSC增殖中的转运独立作用，为Nups在大脑发育中的生理功能提供了见解。原文链接https://doi.org/10.1016/j.devcel.2024.01.002责编|探索君排版|探索君文章来源|“iNature”End往期精选围观Nat Med | 黄荷凤院士/张静澜/徐晨明团队发表综合性无创产前筛查临床研究成果热文Science最新发布：全世界最前沿的125个科学问题热文Nature | 2024年值得关注的七项技术热文新发现推翻古老假说：梅毒微生物家族与人类共存已有数千年热文Nat Methods | 自主生物发光成像技术在真核生物中的创新进展

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