更新于：2024-05-01

FNTB

farnesyltransferase, CAAX box, beta

更新于：2024-05-01

基本信息

别名

CAAX farnesyltransferase subunit beta、farnesyltransferase, CAAX box, beta、FNTB

+ [4]

简介

Essential subunit of the farnesyltransferase complex. Catalyzes the transfer of a farnesyl moiety from farnesyl diphosphate to a cysteine at the fourth position from the C-terminus of several proteins having the C-terminal sequence Cys-aliphatic-aliphatic-X.

关联

100 项与 FNTB 相关的临床结果

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100 项与 FNTB 相关的转化医学

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0 项与 FNTB 相关的专利（医药）

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项与 FNTB 相关的文献（医药）

2023-07-11·Journal of periodontology

Prenyltransferase gene expression reveals an essential role of prenylation for the inflammatory response in human gingival fibroblasts.

Article

作者: Daniel Diehl ; Anton Friedmann ; Hagen S Bachmann

BACKGROUND:

Prenyltrasferases (PTases) are a class of enzymes known to be responsible for promoting posttranslational modification at the carboxyl terminus of proteins containing a so-called CaaX-motif. The process is responsible for proper membrane localization and the appropriate function of several intracellular signaling proteins. Current research demonstrating the pathomechanistic importance of prenylation in inflammatory illnesses emphasizes the requirement to ascertain the differential expression of PT genes under inflammatory settings, particularly in periodontal disease.

METHODS:

Telomerase-immortalized human gingival fibroblasts (HGF-hTert) were cultured and treated with either inhibitors of prenylation (PTI) lonafarnib, tipifarnib, zoledronic acid, or atorvastatin at concentrations of 10 μM in combination with or without 10 μg Porphyromonas gingivalis lipopolysaccharide (LPS) for 24 h. Prenyltransferase genes FNTB, FNTA, PGGT1B, RABGGTA, RABGGTB, and PTAR1 as well as inflammatory marker genes MMP1 and IL1B were detected using quantitative real-time polymerase chain reaction (RT-qPCR). Immunoblot and protein immunoassay were used to confirm the results on the protein level.

RESULTS:

RT-qPCR experiments revealed significant upregulation of IL1B, MMP1, FNTA, and PGGT1B upon LPS treatment. PTase inhibitors caused significant downregulation of the inflammatory cytokine expression. Interestingly, FNTB expression was significantly upregulated in response to any PTase inhibitor in combination with LPS, but not upon LPS treatment only, indicating a vital role of protein farnesyltransferase in the proinflammatory signaling cascade.

CONCLUSIONS:

In this study, distinct PTase gene expression patterns in pro-inflammatory signaling were discovered. Moreover, PTase inhibiting drugs ameliorated inflammatory mediator expression by a significant margin, indicating that prenylation is a major pre-requisite for innate immunity in periodontal cells.

2023-06-14·Molecular & cellular proteomics : MCP

Prenylated PALM2 Promotes the Migration of Esophageal Squamous Cell Carcinoma Cells through Activating Ezrin.

Article

作者: Dan-Xia Deng ; Cheng-Yu Li ; Zhen-Yuan Zheng ; Bing Wen ; Lian-Di Liao ; Xiao-Jun Zhang ; En-Min Li ; Li-Yan Xu

Proteins containing a CAAX motif at the C-terminus undergo prenylation for localization and activity, and include a series of key regulatory proteins, such as RAS superfamily members, heterotrimeric G proteins, nuclear lamina protein, and several protein kinases and phosphatases. However, studies of prenylated proteins in esophageal cancer are limited. Here, through research on large-scale proteomic data of esophageal cancer in our laboratory, we found that paralemmin-2 (PALM2), a potential prenylated protein, was up-regulated and associated with poor prognosis of patients. Low throughput verification showed that the expression of PALM2 in esophageal cancer tissues was higher than that in their paired normal esophageal epithelial tissues, and it was generally expressed in the membrane and cytoplasm of esophageal cancer cells. PALM2 interacted with the two subunits of farnesyl transferase (FTase), FNTA and FNTB. Either addition of an FTase inhibitor or mutation in the CAAX motif of PALM2 (PALM2^C408S) impaired its membranous localization reduced the membrane location of PALM2, indicating PALM2 was prenylated by FTase. Overexpression of PALM2 enhanced the migration of esophageal squamous cell carcinoma (ESCC) cells, whereas PALM2^C408S lost this ability. Mechanistically, PALM2 interacted with the N-terminal FERM domain of ezrin of the ezrin/radixin/moesin (ERM) family. Mutagenesis indicated that lysine residues K253/K254/K262/K263 in ezrin's FERM domain and C408 in PALM2's CAAX motif were important for PALM2/ezrin interaction and ezrin activation. Knockout of ezrin prevented enhanced cancer cell migration by PALM2 overexpression. PALM2, depending on its prenylation, increased both ezrin membrane localization and phosphorylation of ezrin at Y146. In summary, prenylated PALM2 enhances the migration of cancer cells through activating ezrin.

2022-06-01·Human molecular genetics

Mutation Burden Analysis of Six Common Mental Disorders in African Americans by Whole Genome Sequencing.

Article

作者: Yichuan Liu ; Hui-Qi Qu ; Xiao Chang ; Jingchun Qu ; Frank D Mentch ; Kenny Nguyen ; Lifeng Tian ; Joseph Glessner ; Patrick M A Sleiman ; Hakon Hakonarson

Mental disorders present a global health concern, with limited treatment options. In today's medical practice, medications such as antidepressants are prescribed not only for depression, but also for conditions such as anxiety and attention deficit hyperactivity disorder (ADHD). Therefore, identifying gene targets for specific disorders is important and offers improved precision. In this study, we performed a genetic analysis of six common mental disorders, ADHD, anxiety, depression, delays in mental developments, intellectual disabilities (ID), and speech/language disorder in the ethnic minority of African Americans (AA) using whole genome sequencing (WGS). WGS data was generated from blood-derived DNA from 4178 AA individuals, including 1384 patients with the diagnosis of at least one mental disorder. Mutation burden analysis was applied based on rare and deleterious mutations in the AA population between cases and controls, and further analyzed in the context of patients with single mental disorder diagnosis. Certain genes uncovered demonstrated significant p values in mutation burden analysis. In addition, exclusive recurrences in specific type of disorder were scanned through gene-drug interaction databases to assess for availability of potential medications. We uncovered 15 genes harboring deleterious mutations, including HMGCR and UST for ADHD; FNTB for anxiety, XIRP2, NPPC, , STK33, PANX1 and NTS for depression; RUNX3, TACR1, and NDUFS7 for delays in mental developments; HPN for ID; COL6A3, DDB1, and NDUFA11 for speech/language disorder. Taken together, we have established critical insight into the development of new precision medicine approaches for mental disorders in African Americans.

项与 FNTB 相关的新闻（医药）

2024-02-04

·生物制药小编

代谢调控T细胞活化结果

T细胞活化主要包括三段信号：第一信号TCR-MHC、第二信号共刺激和第三信号细胞因子信号转导。大量的证据表明，T细胞的反应在很大程度上依赖于代谢产物的可及性。并且代谢物会通过营养感知和其他机制传递自己的信号。代谢在T细胞活化中的作用：①代谢物不仅是T细胞活化每一个阶段中的基本媒介，而且还提供各自的离散信号来控制T细胞的激活。②代谢物并不只是简单地传播核心T细胞信号，而是将它们自己的偏向传递给CD4+和CD8+ T细胞反应的功能结果。代谢物与T细胞免疫的相互作用不是中性的，某些代谢物的功能偏向决定了T细胞的激活。Nat Immunol.（一）代谢调节TCR信号氨基酸的可获得性会调节TCR的激活和免疫突触的形成。例如：细胞外天冬酰胺水平的增加提高了CD8+T细胞的激活初期和抗肿瘤细胞的效应功能。激活的T细胞对精氨酸的摄取比初始T细胞高得多，细胞内的精氨酸储存在T细胞激活后迅速代谢，从而影响T细胞存活和抗肿瘤功能。T细胞激活过程中会通过Myc20依赖而增加对谷氨酰胺的摄取。在中心，近端抗原特异性信号则被天冬酰胺增强，天冬酰胺促进LCK活性，而镁离子帮助LFA-1进入其活性构象，从而促进与靶细胞更强的附着。不过T细胞在激活过程中对氨基酸的代谢需求通常是时间依赖性的。此外，ROS可降低SHP1的活化，从而促进近端TCR信号强度。肌动蛋白细胞骨架重排则受到溶血磷脂酸和GML等几种代谢物的影响。金属离子代谢：无镁条件下活化的CD8+T细胞代谢流和细胞因子释放较差。镁与LFA-1的两个亚基上的金属离子依赖的黏附部位结合，促进其活跃的“延伸”构象，从而使CD8+T细胞能够完全激活.锌内流在TCR信号转导和激活中也起着关键作用。TCR结扎后增加的锌内流减少了磷酸酶SHP1对TCR激活复合体的募集，并增加了ZAP70的磷酸化。代谢物钙离子同时还是TCR信号的特征之一，在TCR信号框架中是一个重要的离散信号。钙流是许多与T细胞激活相关的代谢变化的关键，可以诱导糖酵解和氧化磷酸化，并反过来受到代谢物的影响。不同的代谢产物对钙的流动有不同的调节作用，例如醋酸盐隔离钙流动，而维生素D促进钙流动。同一样代谢物的具体作用效果也受到细胞环境和暴露剂量的影响。例如，短链脂肪酸醋酸酯可以在TME中促进肿瘤浸润性淋巴细胞的效应功能，还能促进CD8+ T细胞的糖酵解，发挥免疫功能。但同时，暴露于高浓度的醋酸盐则会抑制钙离子流动，从而抑制CD8+ T细胞糖酵解。（二）代谢通过PI3K-AKT-mTOR通路调节共刺激信号。代谢物反馈并调节PI3K途径，PI3K途径激活会启动下游一系列信号，包括丝氨酸/苏氨酸激酶AKT的激活、NFAT核定位和mTOR激酶活性激活。每种代谢物则会向下游信号施加其独特的偏向，以影响T细胞的反应。PI3K-AKT糖酵解代谢过程在TCR激活后迅速上调促进PI3K活性，而磷脂酸和NAC促进AKT激活，从而进一步放大PI3K-AKT-mTOR信号通路。PI3K信号驱动维持强PI3K信号所需的代谢燃料的激活。甲氧丙戊酸代谢和丁酸则通过驱动mTORC1活性，提高T细胞初始激活时的翻译活性。维A酸(retinoic acid，RA)通过AKT信号和mTOR激活实现对CD4+ T细胞的激活作用。由于RA与RARα结合促进RARα的核定位，高浓度RA有利于RA介导的由核RARα介导的Treg细胞分化，而低浓度RA则通过T细胞代谢和Th17细胞介导的炎症反应促进高PI3K-AKT信号的表达。同时，LDHA缺乏的CD8+T细胞通过糖酵解产生的ATP减少，选择性地削弱PI3K依赖的信号，而使近端TCR信号不受影响。作为正反馈回路的一部分，AKT信号调节葡萄糖摄取。静息T细胞中AKT的结构性激活增加了葡萄糖摄取，但与CD28刺激的细胞中的葡萄糖摄取水平不匹配。磷脂酶D-1(PLD1)也促进T细胞激活过程中的AKT激活。mTORmTOR在PI3K-AKT信号下游被激活，但也受到许多代谢物的直接调节。鉴于mTOR是T细胞激活开始时的一个关键代谢开关，T细胞对外部来源代谢物对mTOR活性的调节高度敏感。因此，许多代谢物，包括氨基酸、脂肪酸和金属离子，都是改变T细胞代谢的离散信号。大多数改变T细胞命运的代谢物特异性信号很可能在mTOR途径内汇聚。氨基酸感应：在CD8+T细胞中，氨基酸缺乏会迅速削弱mTOR活性。缺乏ASCT2的CD4+T细胞对谷氨酰胺和亮氨酸的摄取减少，从而抑制mTORC1的激活，这可以通过摄入过量的谷氨酰胺或亮氨酸来弥补。氨基酸转运体LAT1介导细胞对组氨酸、苯丙氨酸和色氨酸等大的中性氨基酸的摄取，是维持CD8+T细胞mTORC1活性的关键。在肿瘤中，与细胞坏死相关的高水平的钾会削弱AKT-mTOR的磷酸化，并在体外和体内抑制CD8+T细胞的反应。钾通道Kv1.3在CD8+T细胞中的过表达增强了它们在肿瘤中的功能，并促进了B16黑色素瘤的清除。mTOR信号还受到脂质衍生的翻译后修饰以及丁酸盐等单链脂肪酸的可及性的影响。依赖Fntb的蛋白质预烯基化在Treg细胞激活期间维持mTORC1的活性。在翻译后修饰之外，用SCFA丁酸盐处理CD4+T细胞可促进mTOR激活。参考文献：1.Wilfahrt, D., Delgoffe, G.M. Metabolic waypoints during T cell differentiation. Nat Immunol (2024). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41590-023-01733-52.Ginefra, P., Hope, H. C., Spagna, M., Zecchillo, A. & Vannini, N. Ionic regulation of T-cell function and anti-tumour immunity. Int. J. Mol. Sci. 22, 13668 (2021).