TM4SF5

更新于：2025-05-07

基本信息

别名

Tetraspan transmembrane protein L6H、TM4SF5、transmembrane 4 L six family member 5

+ [1]

简介

Acts as a lysosomal membrane arginine sensor (PubMed:30956113). Forms a complex with MTOR and SLC38A9 on lysosomal membranes in an arginine-regulated manner, leading to arginine efflux which enables the activation of mTORC1 which subsequently leads to RPS6KB1 and EIF4EBP1 phosphorylations (PubMed:30956113). Facilitates cell cycle G1/S phase progression and the translocation of the CDK4-CCND1 complex into the nucleus (PubMed:20399237). CDKN1B and RHOA/ROCK signaling activity are involved in TM4SF5-mediated acceleration of G1/S phase progression (PubMed:20399237).

关联

100 项与 TM4SF5 相关的临床结果

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100 项与 TM4SF5 相关的转化医学

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0 项与 TM4SF5 相关的专利（医药）

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项与 TM4SF5 相关的文献（医药）

2024-12-01·Life Sciences

Association between hepatocyte TM4SF5 expression and gut microbiome dysbiosis during non-alcoholic fatty liver disease development

Article

作者: Pinanga, Yangie Dwi ; Kim, Soyeon ; Lee, Eun Hae ; Lee, Haesong ; Pyo, Kyung-hee ; Kim, Ji Eon ; Kim, Semi ; Pyo, Kyung-Hee ; Shin, Eun-Ae ; Kim, Wonsik ; Lee, Jung Weon

Gut microbiome dysbiosis is involved in non-alcoholic fatty liver disease (NAFLD) development. Hepatic transmembrane 4 L six family member 5 (TM4SF5) overexpression promotes NAFLD. However, how gut microbiota are associated with TM4SF5-mediated NAFLD remains unexplored. We analyzed the gut microbiome using feces from hepatocyte-specific TM4SF5-overexpressing transgenic (Alb-TG^Tm4sf5^-Flag, TG) or Tm4sf5^-/- knock-out (KO) mice fed a normal chow diet (NCD), high-fat diet (HFD) for 2 weeks (HFD_2W), or methionine-choline-deficient diet (MCD) for 4 weeks to investigate associations among Tm4sf5 expression, diet, and the gut microbiome. TG-NCD mice showed a higher Firmicutes-to-Bacteroidetes (F/B) ratio, with less enrichment of Akkermansia muciniphila and Lactobacillus reuteri. NASH-related microbiomes in feces were more abundant in TG-HFD_2w mice than in KO-HFD_2w mice. Further, TG-MCD showed a higher F/B ratio than TG-NCD or KO mice, with decreases or increases in microbiomes beneficial or detrimental to the liver, respectively. Such effects in TG-MCD animals were correlated with functional pathways producing short-chain fatty acids (SCFAs). Furthermore, potential functional pathways of the gut microbiome were metabolically parallel to NAFLD features in TG-MCD mice. These results suggest that hepatocyte Tm4sf5 supports gut microbiome dysbiosis and metabolic activity, leading to SCFA production and hepatic inflammation during NAFLD development.

2024-01-01·Cancer Communications

Glucose‐mediated mitochondrial reprogramming by cholesterol export at TM4SF5‐enriched mitochondria‐lysosome contact sites

Article

作者: Jun, Chang-Duck ; Liu, Kwang-Hyeon ; Kwak, Chulhwan ; Kim, Ji Eon ; Rhee, Hyun-Woo ; Yun, Jeanho ; Kim, Wonsik ; Pyo, Kyung-Hee ; Pinanga, Yangie ; Lee, Yoonji ; Jung, Jae Woo ; Kim, Soyeon ; Lee, Haesong ; Lee, Jung Weon ; Choi, Sun ; Shin, Eun-Ae ; Park, So-Young ; Song, Dae-Geun ; Lee, Eun Hae

AbstractBackgroundTransmembrane 4 L six family member 5 (TM4SF5) translocates subcellularly and functions metabolically, although it is unclear how intracellular TM4SF5 translocation is linked to metabolic contexts. It is thus of interests to understand how the traffic dynamics of TM4SF5 to subcellular endosomal membranes are correlated to regulatory roles of metabolisms.MethodsHere, we explored the metabolic significance of TM4SF5 localization at mitochondria‐lysosome contact sites (MLCSs), using in vitro cells and in vivo animal systems, via approaches by immunofluorescence, proximity labelling based proteomics analysis, organelle reconstitution etc.ResultsUpon extracellular glucose repletion following depletion, TM4SF5 became enriched at MLCSs via an interaction between mitochondrial FK506‐binding protein 8 (FKBP8) and lysosomal TM4SF5. Proximity labeling showed molecular clustering of phospho‐dynamic‐related protein I (DRP1) and certain mitophagy receptors at TM4SF5‐enriched MLCSs, leading to mitochondrial fission and autophagy. TM4SF5 bound NPC intracellular cholesterol transporter 1 (NPC1) and free cholesterol, and mediated export of lysosomal cholesterol to mitochondria, leading to impaired oxidative phosphorylation but intact tricarboxylic acid (TCA) cycle and β‐oxidation. In mouse models, hepatocyte Tm4sf5 promoted mitophagy and cholesterol transport to mitochondria, both with positive relations to liver malignancy.ConclusionsOur findings suggested that TM4SF5‐enriched MLCSs regulate glucose catabolism by facilitating cholesterol export for mitochondrial reprogramming, presumably while hepatocellular carcinogenesis, recapitulating aspects for hepatocellular carcinoma metabolism with mitochondrial reprogramming to support biomolecule synthesis in addition to glycolytic energetics.

2023-09-01·iScience

TM4SF5-mediated abnormal food-intake behavior and apelin expression facilitate non-alcoholic fatty liver disease features

Article

作者: Pinanga, Yangie Dwi ; Lee, Haesong ; Kim, Ji Eon ; Kim, Hwi Young ; Lee, Han Ah ; Pyo, Kyung-Hee ; Shin, Eun-Ae ; Kim, Wonsik ; Lee, Eun Hae ; Kim, Soyeon ; Lee, Jung Weon

Transmembrane 4 L six family member 5 (TM4SF5) engages in non-alcoholic steatohepatitis (NASH), although its mechanistic roles are unclear. Genetically engineered Tm4sf5 mice fed ad libitum normal chow or high-fat diet for either an entire day or a daytime-feeding (DF) pattern were analyzed for metabolic parameters. Compared to wild-type and Tm4sf5^-/- knockout mice, hepatocyte-specific TM4SF5-overexpressing Alb-TG^Tm4sf5-Flag (TG) mice showed abnormal food-intake behavior during the mouse-inactive daytime, increased apelin expression, increased food intake, and higher levels of NASH features. DF or exogenous apelin injection of TG mice caused severe hepatic pathology. TM4SF5-mediated abnormal food intake was correlated with peroxisomal β-oxidation, mTOR activation, and autophagy inhibition, with triggering NASH phenotypes. Non-alcoholic fatty liver disease (NAFLD) patients' samples revealed a correlation between serum apelin and NAFLD activity score. Altogether, these observations suggest that hepatic TM4SF5 may cause abnormal food-intake behaviors to trigger steatohepatitic features via the regulation of peroxisomal β-oxidation, mTOR, and autophagy.

项与 TM4SF5 相关的新闻（医药）

2025-01-26

·奇点网

提升NK细胞对肝癌免疫监视的新路子

*仅供医学专业人士阅读参考我们知道，肝脏作为营养代谢和毒素清除的核心器官，同时也具备强大的免疫监视功能，其中自然杀伤（NK）细胞更是占到了肝脏淋巴细胞的50%左右。但遗憾的是，这并不能阻止肝脏肿瘤的发生和进展。而肝脏肿瘤一旦发生，就说明癌细胞已经逃脱了肝脏中大量NK细胞的监视，那么癌细胞究竟是如何做到的呢？这背后的机制又是什么呢？近期，韩国首尔大学Jung Weon Lee团队与韩国车医科大学（CHA）Young-Ger Suh团队联合发表了一项研究成果。他们揭示了，一种在肝细胞癌（HCC）组织中高度表达的跨膜蛋白TM4SF5，通过触发NK细胞刺激性配体SLAMF7的降解，促进HCC发生发展的关键机制。具体来说，研究人员发现，TM4SF5会以N-糖基化的方式与SLAMF7结合，诱导其从细胞膜向溶酶体转运并降解。这一过程削弱了SLAMF7对NK细胞活性的刺激作用，抑制了NK细胞对肿瘤的免疫监视功能，从而推动了HCC的发生和发展。而使用针对TM4SF5的异噁唑小分子抑制剂（TSIs），如ST-5-002，可以有效阻断TM4SF5与SLAMF7的结合，恢复SLAMF7在细胞膜上的表达，进一步增强了NK细胞的活性，并成功抑制了小鼠HCC的进展。研究发表在Signal Transduction and Targeted Therapy上[1]。论文首页截图事实上，既往已有研究显示，TM4SF5作为一种N-糖基化膜蛋白，可以通过抑制NK细胞的活性来促进HCC的进展，但是这背后的机制，以及针对TM4SF5的治疗能否提升NK细胞的活性和对HCC的免疫监视作用，还不清楚。在本研究中，研究人员先是通过体外实验发现，TM4SF5过表达会降低MICA/B、SLAMF7等NK细胞刺激配体的表达，而TM4SF5敲除则增强了这些配体的水平。接下来的体内分析则显示，在TM4SF5过表达的小鼠肝组织中，NK细胞的活性会出现明显降低（表现为颗粒酶和穿孔素水平的显著降低）。TM4SF5介导NK细胞失活而进一步的临床数据则发现，高TM4SF5表达和低SLAMF7表达的HCC患者生存率普遍较差，而其他NK细胞配体的表达降低则与患者生存概率无显著关联。以上这些结果表明，TM4SF5主要通过下调NK细胞刺激配体SLAMF7的表达水平，导致NK细胞失活，从而促进HCC的发展。临床分析结果通过免疫荧光等一系列实验，研究人员发现，机制上，TM4SF5会以依赖N-糖基化的方式与SLAMF7结合，诱导其从细胞膜向溶酶体转运并降解。这一过程削弱了SLAMF7对NK细胞活性的刺激作用，抑制了NK细胞对肿瘤的免疫监视功能，从而推动了HCC的发生和发展。研究机制图根据以上机制，研究人员利用综合结构-活性关系分析鉴定出了一类可以特异性与TM4SF5结合的异噁唑结构的小分子抑制剂（TSIs，如ST-2-001、ST-5-002，其中ST-5-002与TM4SF5结合能力更强）。ST-2-001和ST-5-002的结构结果发现，TSIs可以有效阻断TM4SF5与SLAMF7的结合，恢复SLAMF7在细胞膜上的表达，进一步增强了NK细胞的活性。此外，在TM4SF5阳性患者来源的异种移植（PDX）模型中，研究人员发现，与对照组相比，接受TSIs治疗（腹腔注射，3天一次，共6次）可以显著抑制小鼠HCC的进展。治疗策略图总之，该研究揭示了TM4SF5通过下调NK细胞刺激配体SLAMF7的表达，削弱NK细胞的免疫监视功能，从而促进HCC进展的机制。而靶向TM4SF5的TSIs则可恢复NK细胞功能，有效抑制HCC进展。这些发现不仅为TM4SF5-SLAMF7轴作为HCC新型免疫检查点的靶向治疗提供了强有力的支持，也为未来开发创新疗法和优化治疗策略提供了坚实基础。参考文献：[1]Kim JE, Kim HS, Kim W, et al. Isoxazole-based molecules restore NK cell immune surveillance in hepatocarcinogenesis by targeting TM4SF5 and SLAMF7 linkage. Signal Transduct Target Ther. 2025;10(1):15. Published 2025 Jan 20. doi:10.1038/s41392-024-02106-6本文作者丨张金旭

细胞疗法临床研究免疫疗法