更新于：2024-11-01

MARCHF2

更新于：2024-11-01

基本信息

别名

E3 ubiquitin-protein ligase MARCHF2、HSPC240、MARCH-II

+ [8]

简介

E3 ubiquitin-protein ligase that may mediate ubiquitination of TFRC and CD86, and promote their subsequent endocytosis and sorting to lysosomes via multivesicular bodies. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates (PubMed:14722266, PubMed:16428329). Together with GOPC/CAL mediates the ubiquitination and lysosomal degradation of CFTR (PubMed:23818989). Ubiquitinates and therefore mediates the degradation of DLG1 (PubMed:17980554). Regulates the intracellular trafficking and secretion of alpha1-antitrypsin/SERPINA1 and HP/haptoglobin via ubiquitination and degradation of the cargo receptor ERGIC3 (PubMed:31142615). Negatively regulates the antiviral and antibacterial immune response by repression of the NF-kB and type 1 IFN signaling pathways, via MARCHF2-mediated K48-linked polyubiquitination of IKBKG/NEMO, resulting in its proteasomal degradation (PubMed:32935379). May be involved in endosomal trafficking through interaction with STX6 (PubMed:15689499). (Microbial infection) Positively regulates the degradation of Vesicular stomatitis virus (VSV) G protein via the lysosomal degradation pathway (PubMed:29573664). Represses HIV-1 viral production and may inhibit the translocation of HIV-1 env to the cell surface, resulting in decreased viral cell-cell transmission (PubMed:29573664).

关联

项与 MARCHF2 相关的药物

CN115212310

专利挖掘

靶点

MARCHF2

作用机制-

在研机构

复旦大学附属中山医院

原研机构

复旦大学附属中山医院

在研适应症

纤维化

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 MARCHF2 相关的临床结果

登录后查看更多信息

100 项与 MARCHF2 相关的转化医学

登录后查看更多信息

0 项与 MARCHF2 相关的专利（医药）

登录后查看更多信息

项与 MARCHF2 相关的文献（医药）

2024-08-01·Veterinary Microbiology

MARCH1 and MARCH2 inhibit pseudorabies virus replication by trapping the viral cell-to-cell fusion complex in trans-Golgi network

Article

作者: Sun, Yue ; Peng, Jin-Mei ; Fandan, Meng ; Tang, Yan-Dong ; Huang, Rui ; Bai, Yuan-Zhe ; Rao, Cui-Hong ; Tian, Zhi-Jun ; Xu, Shi-Jia ; Cai, Xue-Hui ; Chen, Meng ; Khan, Mirwaise ; Lyu, Chuang ; Yu, Changqing ; An, Tong-Qing ; Wang, Gang

The membrane-associated RING-CH (MARCH) family of proteins are members of the E3 ubiquitin ligase family and are essential for a variety of biological functions. Currently, MARCH proteins are discovered to execute antiviral functions by directly triggering viral protein degradation or blocking the furin cleavage of viral class I fusion proteins. Here, we report a novel antiviral mechanism of MARCH1 and MARCH2 (MARCH1/2) in the replication of Pseudorabies virus (PRV), a member of the Herpesviridae family. We discovered MARCH1/2 restrict PRV replication at the cell-to-cell fusion step. Furthermore, MARCH1/2 block gB cleavage, and this is dependent on their E3 ligase activity. Interestingly, the blocking of gB cleavage by MARCH1/2 does not contribute to their antiviral activity in vitro. We discovered that MARCH1/2 are associated with the cell-to-cell fusion complex of gB, gD, gH, and gL and trap these viral proteins in the trans-Golgi network (TGN) rather than degrading them. Overall, we conclude that MARCH1/2 inhibit PRV by trapping the viral cell-to-cell fusion complex in TGN.

2024-07-01·Experimental Cell Research

KLF15-activated MARCH2 boosts cell proliferation and epithelial-mesenchymal transition and presents diagnostic significance for hepatocellular carcinoma

Article

作者: Man, Yong ; Ni, Dongsheng ; Chen, Jingzhou ; Wang, Yuefeng ; Li, Guoping ; Li, Jian ; Qi, Zhaolai ; Pang, Jing ; Tang, Weiqing

PURPOSEMembrane associated ubiquitin ligase MARCH2 majorly involves in inflammation response and protein trafficking. However, its comprehensive role in hepatocellular carcinoma (HCC) is largely unknown.METHODSFirstly, multiple bioinformatic analyses were applied to determine MARCH2 mRNA level, its expression comparison in diverse molecular and immune subtypes, and diagnostic value in HCC. Subsequently, RNA-seq, real-time quantitative PCR, immunohistochemistry and cell proliferation assay are used to explore the epithelial-mesenchymal transition (EMT) and proliferation by gene-silencing or overexpressing in cultured HCC cells or in vivo xenograft. Moreover, dual luciferase reporter assay and immunoblotting are delved into verify the transcription factor that activating MARCH2 promoter.RESULTSMultiple bioinformatic analyses demonstrate that MARCH2 is upregulated in multiple cancer types and exhibits startling diagnostic value as well as distinct molecular and immune subtypes in HCC. RNA-seq analysis reveals MARCH2 may promote EMT, cell proliferation and migration in HepG2 cells. Furthermore, overexpression of MARCH2 triggers EMT and significantly enhances HCC cell migration, proliferation and colony formation in a ligase activity-dependent manner. Additionally, above observations are validated in the HepG2 mice xenografts. For up-stream mechanism, transcription factor KLF15 is highly expressed in HCC and activates MARCH2 expression.CONCLUSIONKLF15 activated MARCH2 triggers EMT and serves as a fascinating biomarker for precise diagnosis of HCC. Consequently, MARCH2 emerges as a promising candidate for target therapy in cancer management.

2024-06-21·Human Molecular Genetics

Colocalization analysis of 3′ UTR alternative polyadenylation quantitative trait loci reveals novel mechanisms underlying associations with lung function

Article

作者: Chase, Robert P ; Castaldi, Peter J ; Xu, Zhonghui ; Saferali, Aabida ; Kim, Wonji ; Cho, Michael H ; Laederach, Alain ; Hersh, Craig P

AbstractWhile many disease-associated single nucleotide polymorphisms (SNPs) are expression quantitative trait loci (eQTLs), a large proportion of genome-wide association study (GWAS) variants are of unknown function. Alternative polyadenylation (APA) plays an important role in posttranscriptional regulation by allowing genes to shorten or extend 3′ untranslated regions (UTRs). We hypothesized that genetic variants that affect APA in lung tissue may lend insight into the function of respiratory associated GWAS loci. We generated alternative polyadenylation (apa) QTLs using RNA sequencing and whole genome sequencing on 1241 subjects from the Lung Tissue Research Consortium (LTRC) as part of the NHLBI TOPMed project. We identified 56 179 APA sites corresponding to 13 582 unique genes after filtering out APA sites with low usage. We found that a total of 8831 APA sites were associated with at least one SNP with q-value < 0.05. The genomic distribution of lead APA SNPs indicated that the majority are intronic variants (33%), followed by downstream gene variants (26%), 3′ UTR variants (17%), and upstream gene variants (within 1 kb region upstream of transcriptional start site, 10%). APA sites in 193 genes colocalized with GWAS data for at least one phenotype. Genes containing the top APA sites associated with GWAS variants include membrane associated ring-CH-type finger 2 (MARCHF2), nectin cell adhesion molecule 2 (NECTIN2), and butyrophilin subfamily 3 member A2 (BTN3A2). Overall, these findings suggest that APA may be an important mechanism for genetic variants in lung function and chronic obstructive pulmonary disease (COPD).

项与 MARCHF2 相关的新闻（医药）

2024-03-03

·今日头条

再次发力！复旦张英梅教授、葛均波院士等合作发文

本文为转化医学网原创，转载请注明出处作者：Sophia 导读：众所周知，炎症小体活化和热噬细胞死亡有助于心血管疾病的发病机制，例如心肌缺血—再灌注（I/R）损伤，但其潜在调节机制仍知之甚少。 2024年2月28日，复旦大学张英梅、葛均波联合中国科学院分子细胞科学卓越创新中心胡荣贵共同在《Cell Discovery》上发表题为“The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis”的研究论文，研究表明E3泛素连接酶MARCH2通过负调控PGAM5/MAVS/NLRP3轴抑制心肌焦亡，保护心肌缺血再灌注损伤。 https://www.nature.com/articles/s41421-023-00622-3 研究背景 01 炎性小体是一种大分子结构，负责感知损伤并引发一系列炎症反应。炎症小体最具特征的传感器是NACHT、LRR和PYD结构域蛋白3 (NLRP3)，它们在无菌炎症反应中被激活。NLRP3炎症小体激活有助于许多炎症性疾病的病理生理学。例如，由损伤相关分子模式（DAMP）激活的 NLRP3 炎症小体参与非酒精性脂肪性肝病的发病机制。此外，发现 NLRP3 和炎性细胞因子 IL-18 和 IL-1β 的表达水平在动脉粥样硬化斑块发展中升高。此外，NLRP3 的敲除（KO）通过消除活性氧（ROS）和线粒体损伤诱发的炎症小体激活来防止高脂肪饮食引起的肥胖和胰岛素抵抗。心肌梗死（MI）仍然是全球残疾和死亡的主要原因之一。及时恢复通过闭塞冠状动脉的血流是心肌梗死患者的最佳操作。然而，这种再灌注可能会激活心肌的级联有害损伤，称为缺血再灌注（I/R）损伤。新出现的证据表明，炎症小体的激活是炎症驱动的心肌 I/R 损伤的一个组成部分。已知抑制 NLRP3 炎症小体激活可限制心肌 I/R 损伤后的梗死面积和心功能障碍。因此，鉴定 NLRP3 炎症小体的内源性调节剂以抑制其激活可能在临床上有益。研究结果 02 我们的研究结果表明，MARCH2 对心肌 I/R 损伤、炎症小体激活和心肌细胞焦亡具有突出的心脏保护作用。MARCH2 在 ICM 患者和 I/R 激发小鼠心脏中上调。MARCH2 消融术加重了 I/R 诱发的心肌损伤，梗死面积、超声心动图参数和心肌细胞力学证明了这一点。我们的进一步分析表明， MARCH2 通过介导其 K48 连接的 polyUb 促进 PGAM5 的降解，以及通过 PGAM5/MAVS/NLRP3 依赖性机制缓解 I/R 损伤后的炎症反应和热沉细胞死亡（图 8j）。特别是，PGAM5-MAVS 缩合物介导 NLRP3 炎症小体的激活，可能充当 PGAM5/MAVS/NLRP3 海绵并促进 GSDMD 和 IL-18 的 caspase-1 依赖性切割。此外，使用 AAV9-cTnT-MARCH2 异位表达 MARCH2 可有效改善 I/R 损伤诱发的心肌损伤。在这种情况下，MARCH2 对 I/R 诱发的心肌损伤有益。 MARCH2 功能在 I/R 损伤中的工作模型。 MARCH2 通过促进 PGAM5 的 K48 连接的 polyUb 与 PGAM5 相互作用并促进其降解，从而抑制 MAVS/NLRP3 炎症小体通路和心肌细胞焦亡的活性。研究结论 03 总之，我们的研究结果不仅确立了 E3 连接酶 MARCH2 作为对抗心肌 I/R 损伤的新型心脏保护分子，而且还确定了一种以前未知的机制，该机制负调控 PGAM5/MAVS/NLRP3 炎症小体信号传导和焦亡，以维持哺乳动物心脏的稳态和正常功能。因此，靶向 MARCH2 可能代表了对抗心肌损伤的新机会。参考资料： https://www.nature.com/articles/s41421-023-00622-3 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 上海｜3月01日-02日 ▶第三届长三角单细胞组学技术应用论坛暨空间组学前沿论坛将在上海召开，诚邀您的参与！点击对应文字查看详情

2024-03-02

·生物探索

Cell Discov | 复旦大学张英梅/葛均波等合作揭示MARCH2对抗心肌缺血再灌注伤害的机制

引言炎症小体激活和焦亡会促进心肌缺血-再灌注(I/R)损伤，但其潜在的调节机制尚不清楚。2024年2月28日，复旦大学张英梅、葛均波及中国科学院分子细胞科学卓越创新中心胡荣贵共同通讯在Cell Discovery（IF 34）在线发表题为“The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis”的研究论文，该研究表明E3泛素连接酶MARCH2通过负调控PGAM5/MAVS/NLRP3轴抑制心肌焦亡，保护心肌缺血再灌注损伤。炎症小体是一种大分子结构，负责感知损伤并引发一系列炎症反应。炎症小体最具特征的传感器是NACHT、LRR和PYD结构域蛋白3 (NLRP3)，它们在无菌炎症反应中被激活。炎症小体传感器NLRP3的激活会募集含有caspase-募集结构域(ASC)和效应蛋白caspase-1的接头凋亡相关斑点样蛋白，通过促进焦亡直接触发严重的组织损伤，并通过IL-18的分泌间接触发。新出现的证据表明，炎症小体的激活是炎症驱动的心肌I/R损伤的一个组成部分。抑制NLRP3炎性小体激活可以限制心肌I/R损伤后的梗死面积和心功能障碍。因此，鉴定内源性NLRP3炎症小体的调节剂以抑制其激活可能对临床有益。I/R损伤中MARCH2功能的工作模型（Credit: Cell Discovery）泛素(Ub)-蛋白酶体系统调节许多细胞过程中的蛋白质降解和稳态。因此，识别关键的泛素化相关调节剂可能减轻心肌I/R损伤。为此，研究人员对心肌I/R损伤小鼠的心脏样本进行了单细胞RNA测序(scRNA-seq)。研究发现E3连接酶膜相关环指蛋白2 (MARCH2)上调，MARCH2是MARCH E3 Ub连接酶亚家族的成员，包括11个成员，主要定位于内质网、核内体、高尔基体、线粒体和质膜。已知MARCH2通过与syntaxin-616相互作用调节核内体和反面高尔基管网结构。之间的囊泡运输以及回收核内体。研究还显示，MARCH2通过促进CFTR的泛素化和降解以及激活PIK3CA-AKT-mTOR通路，负向调节肿瘤细胞的自噬。利用MARCH2 KO和AAV9cTnT-MARCH2转染小鼠模型，该研究表明，MARCH2改善心肌I/R损伤并抑制NLRP3炎症小体的激活。研究发现，MARCH2与磷酸甘油酸突变酶家族成员5 (PGAM5)相互作用，促进其与K48相关的泛素化和降解。PGAM5的泛素非依赖性降解导致PGAM5-线粒体抗病毒信号蛋白(MAVS)相分离凝聚物的抑制和下游NLRP3炎症小体的激活。这些发现证明了MARCH2作为心肌I/R损伤的新治疗靶点的重要作用。原文链接https://www.nature.com/articles/s41421-023-00622-3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Nature | 癌症与神经系统的致命舞蹈

蛋白降解靶向嵌合体