更新于：2024-11-01

EMC10

更新于：2024-11-01

基本信息

别名

C19orf63、EMC10、ER membrane protein complex subunit 10

+ [4]

简介

Part of the endoplasmic reticulum membrane protein complex (EMC) that enables the energy-independent insertion into endoplasmic reticulum membranes of newly synthesized membrane proteins (PubMed:30415835, PubMed:29809151, PubMed:29242231, PubMed:32459176, PubMed:32439656). Preferentially accommodates proteins with transmembrane domains that are weakly hydrophobic or contain destabilizing features such as charged and aromatic residues (PubMed:30415835, PubMed:29809151, PubMed:29242231). Involved in the cotranslational insertion of multi-pass membrane proteins in which stop-transfer membrane-anchor sequences become ER membrane spanning helices (PubMed:30415835, PubMed:29809151). It is also required for the post-translational insertion of tail-anchored/TA proteins in endoplasmic reticulum membranes (PubMed:29809151, PubMed:29242231). By mediating the proper cotranslational insertion of N-terminal transmembrane domains in an N-exo topology, with translocated N-terminus in the lumen of the ER, controls the topology of multi-pass membrane proteins like the G protein-coupled receptors (PubMed:30415835). By regulating the insertion of various proteins in membranes, it is indirectly involved in many cellular processes (Probable). Promotes angiogenesis and tissue repair in the heart after myocardial infarction. Stimulates cardiac endothelial cell migration and outgrowth via the activation of p38 MAPK, PAK and MAPK2 signaling pathways (PubMed:28931551).

关联

项与 EMC10 相关的药物

CN114149500

专利挖掘

靶点

EMC10

作用机制-

在研机构

复旦大学附属华山医院 [+1]

原研机构

Huaan Bioall (Shanghai) Biotechnology Co., Ltd. [+1]

在研适应症

肿瘤

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

WO2022048577

专利挖掘

靶点

EMC10

作用机制-

在研机构

复旦大学附属华山医院

原研机构

复旦大学附属华山医院

在研适应症

肿瘤

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 EMC10 相关的临床结果

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100 项与 EMC10 相关的转化医学

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0 项与 EMC10 相关的专利（医药）

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项与 EMC10 相关的文献（医药）

2024-09-01·Journal of Hepatology

EMC10 modulates hepatic ER stress and steatosis in an isoform-specific manner

Article

作者: Dietrich, Arne ; Jin, Shuoshuo ; Miao, Qing ; Liu, Xiaoxia ; Chen, Lijiao ; Liu, Yuzhao ; Wang, Xuanchun ; Liew, Chong Wee ; Dai, Jiarong ; Liu, Shan ; Blüher, Matthias ; Liu, Chuanfeng ; Yang, Jia ; Chen, Kuangyang ; Wang, Yangang ; Wang, Yahao ; Yu, Yongzhuo ; Klöting, Nora

BACKGROUND & AIMSEndoplasmic reticulum (ER) membrane protein complex subunit 10 (EMC10) has been implicated in obesity. Here we investigated the roles of the two isoforms of EMC10, including a secreted isoform (scEMC10) and an ER membrane-bound isoform (mEMC10), in metabolic dysfunction-associated steatotic liver disease (MASLD).METHODSManifold steatotic mouse models and HepG2 cells were employed to investigate the role of EMC10 in the regulation of hepatic PERK-eIF2α-ATF4 signaling and hepatosteatosis. The therapeutic effect of scEMC10-neutralizing antibody on mouse hepatosteatosis was explored. Associations of MASLD with serum scEMC10 and hepatic mEMC10 were determined in two cohorts of participants with MASLD.RESULTSscEMC10 promoted, while mEMC10 suppressed, the activation of hepatic PERK-eIF2α-ATF4 signaling. Emc10 gene knockout exacerbated, while hepatic overexpression of mEMC10 ameliorated, hepatic ER stress and steatosis in mice challenged with either a methionine- and choline-deficient diet or tunicamycin, highlighting a direct, suppressive role of mEMC10 in MASLD via modulation of hepatic ER stress. Overexpression of scEMC10 promoted, whereas neutralization of circulating scEMC10 prevented, hepatosteatosis in mice with fatty liver, suggesting a role of scEMC10 in MASLD development. Clinically, serum scEMC10 was increased, while hepatic mEMC10 was decreased, in participants with MASLD. Correlative analysis indicated that serum scEMC10 positively, whereas hepatic mEMC10 negatively, correlated with liver fat content and serum ALT, AST, and GGT.CONCLUSIONSThese findings demonstrate a novel isoform-specific role for EMC10 in the pathogenesis of MASLD and identify the secreted isoform as a tractable therapeutic target for MASLD via antibody-based neutralization.IMPACT AND IMPLICATIONSWe have shown the role of EMC10 in the regulation of energy homeostasis and obesity. In this study, we determine the distinct roles of the two isoforms of EMC10 in the regulation of hepatic endoplasmic reticulum stress and steatosis in mice, and report on the associations of the different EMC10 isoforms with metabolic dysfunction-associated steatotic liver disease in humans. Our findings delineate a novel regulatory axis for hepatosteatosis and identify EMC10 as a modulator of the PERK-eIF2α-ATF4 signaling cascade that may be of broad physiological significance. Moreover, our pre-clinical and clinical studies provide evidence of the therapeutic potential of targeting scEMC10 in MASLD.

2024-08-01·Journal of Chromatography A

Improved hydrophobic subtraction model of reversed-phase liquid chromatography selectivity based on a large dataset with a focus on isomer selectivity

Article

作者: Dahlseid, Tina ; Zhou, Yiyang ; Kruger, Zachary ; Rutan, Sarah C ; Wang, Qinggang ; Stoll, Dwight R ; Kempen, Trevor ; Shackman, Jonathan G ; Pirok, Bob

Reversed-phase (RP) liquid chromatography is an important tool for the characterization of materials and products in the pharmaceutical industry. Method development is still challenging in this application space, particularly when dealing with closely-related compounds. Models of chromatographic selectivity are useful for predicting which columns out of the hundreds that are available are likely to have very similar, or different, selectivity for the application at hand. The hydrophobic subtraction model (HSM1) has been widely employed for this purpose; the column database for this model currently stands at 750 columns. In previous work we explored a refinement of the original HSM1 (HSM2) and found that increasing the size of the dataset used to train the model dramatically reduced the number of gross errors in predictions of selectivity made using the model. In this paper we describe further work in this direction (HSM3), this time based on a much larger solute set (1014 solute/stationary phase combinations) containing selectivities for compounds covering a broader range of physicochemical properties compared to HSM1. The molecular weight range was doubled, and the range of the logarithm of the octanol/water partition coefficients was increased slightly. The number of active pharmaceutical ingredients and related synthetic intermediates and impurities was increased from four to 28, and ten pairs of closely related structures (e.g., geometric and cis-/trans- isomers) were included. The HSM3 model is based on retention measurements for 75 compounds using 13 RP stationary phases and a mobile phase of 40/60 acetonitrile/25 mM ammonium formate buffer at pH 3.2. This data-driven model produced predictions of ln α (chromatographic selectivity using ethylbenzene as the reference compound) with average absolute errors of approximately 0.033, which corresponds to errors in α of about 3 %. In some cases, the prediction of the trans-/cis- selectivities for positional and geometric isomers was relatively accurate, and the driving forces for the observed selectivity could be inferred by examination of the relative magnitudes of the terms in the HSM3 model. For some geometric isomer pairs the interactions mainly responsible for the observed selectivities could not be rationalized due to large uncertainties for particular terms in the model. This suggests that more work is needed in the future to explore other HSM-type models and continue expanding the training dataset in order to continue improving the predictive accuracy of these models. Additionally, we release with this paper a much larger data set (43,329 total retention measurements) at multiple mobile phase compositions, to enable other researchers to pursue their own lines of inquiry related to RP selectivity.

2024-06-01·Prenatal Diagnosis

Novel compound heterozygous variants in EMC1: Overlapping phenotypes of left ventricular noncompaction and long QT syndrome warranting in‐depth exploration

Article

作者: Wang, Yu ; Chen, Jiao ; Liu, Hanmin ; Dai, Xiaohui

AbstractA couple was referred for prenatal counseling at the gestational age of 35 weeks of a male fetus (II‐2) with sinus bradycardia and suspected first degree atrioventricular block with left ventricular noncompaction (LVNC). A previous pregnancy for the couple of a female fetus (II‐1) was diagnosed prenatally as sinus bradycardia at the gestational age of 30 weeks. Both fetuses were confirmed to have long QT syndrome (LQTS) with LVNC after birth, and died of heart failure during infancy. The genetic cause of the combined cardiovascular disorders was investigated by trio whole‐exome sequencing and Sanger sequencing on DNA extracted from parental blood samples and umbilical cord serum of the proband. Compound heterozygous variants were identified in the endoplasmic reticulum membrane protein complex subunit 1 gene (EMC1, NM_015047.3), including paternally inherited c.245C>T (p. Thr82Met) and maternally inherited c.1459delC (p. Arg487Alafs*49). Pathogenic variants in EMC1 have been associated with a recessive neurodevelopmental disorder, whereas Emc10 knockout mice exhibit cardiovascular issues. The present study shows that EMC1 variation potentially causes the overlapping phenotypes of LVNC and LQTS and may expand the spectrum of diseases caused by EMC1 variation.

项与 EMC10 相关的新闻（医药）

2024-04-10

·生物探索

J Hepatol | 复旦大学王宣春团队发现调节肝脏内质网应激和脂肪变性的新机制

引言内质网(ER)膜蛋白复合物亚基10 (EMC10)与肥胖有关。2024年4月7日，复旦大学王宣春团队在Journal of Hepatology（IF 26）在线发表题为“EMC10 modulates hepatic ER stress and steatosis in an isoform specific manner”的研究论文，该研究发现EMC10以同种异构体特异性的方式调节肝脏内质网应激和脂肪变性。scEMC10促进了肝细胞PERK-eIF2α-ATF4信号的激活，而mEMC10抑制了这些信号的激活。在MCD饮食或tunicamycin刺激的小鼠中，Emc10基因敲除加剧了这种情况，而肝脏过表达mEMC10改善了肝脏内质网应激和脂肪变性，突出了mEMC10通过调节肝脏内质网应激在MASLD中的直接抑制作用。在脂肪肝小鼠中，过表达scEMC10可促进肝纤维化，而循环中和scEMC10可阻止肝纤维化，这表明scEMC10在MASLD中具有进行性作用。临床上，MASLD患者血清scEMC10升高，而肝脏mEMC10降低。相关分析显示，血清scEMC10与肝脏脂肪含量及血清ALT、AST、GGT呈显著正相关，而肝脏mEMC10与肝脏脂肪含量及血清ALT、AST、GGT呈显著负相关。这些发现证明了 EMC10在 MASLD 发病机制中具有新的亚型特异性作用，并通过基于抗体的中和将分泌的亚型确定为 MASLD 的可处理治疗靶点。内质网应激与多种代谢疾病有关，包括代谢功能障碍相关的脂肪变性肝病(MASLD)。在内质网应激的情况下，一种被称为未折叠蛋白反应(UPR)的适应性机制被激活，并在适度和充分运作的情况下对肝细胞发挥保护作用。然而，长时间或严重的UPR会导致脂肪肝的发展，即MASLD的初级阶段。脂肪变性反过来又加剧内质网应激，形成脂肪肝和内质网应激之间的恶性循环。PERK-eIF2α-ATF4通路是UPR的一个分支，已被广泛研究与脂肪肝有关。在人类中，eIF2α磷酸化在脂肪肝中增加，并随着体重减轻而减少脂肪变性。在小鼠中，脂肪肝中也观察到肝脏eIF2α磷酸化升高，持续的肝脏eIF2α去磷酸化可减轻HFD诱导的脂肪肝。在小鼠和斑马鱼中，ATF4消融可预防脂肪肝，而过表达可促进脂肪肝。内质网膜蛋白复合物(EMC)在内质网应激、膜蛋白转运异常和内质网降解等细胞过程中起调节作用。EMC10是EMC的一个亚基，在人和啮齿类动物中有两个亚型，包括分泌型亚型(scEMC10)和内质网膜结合型亚型 (mEMC10)。先前已经证明，EMC10 的两种同工型在男性生育能力中发挥了不同的作用。此外，最近的研究表明scEMC10过表达促进，而循环 scEMC10或Emc10基因敲除(Emc10 KO)的抗体中和可预防小鼠饮食性肥胖、胰岛素抵抗、葡萄糖耐受不良和脂肪肝。在临床上，肥胖患者血清scEMC10升高，与胰岛素抵抗和BMI呈正相关，而与人类静息代谢率呈负相关。EMC10的两种亚型在脂肪肝发病机制中的作用（Credit: Journal of Hepatology）该研究表明，scEMC10促进，而mEMC10抑制小鼠肝细胞PERK-eIF2α-ATF4信号通路的激活和其相关的脂肪肝，这进一步得到临床研究结果的支持，血清scEMC10与人MASLD呈正相关，而肝脏mEMC10与呈负相关。这项工作区分了EMC10 527的两种亚型在MASLD中的作用，并确定了scEMC10是MASLD的一个有希望的治疗靶点。原文链接https://doi.org/10.1016/j.jhep.2024.03.047责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

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