TM4SF5

Last update 08 May 2025

Basic Info

Synonyms

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

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Introduction

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).

100 Clinical Results associated with TM4SF5

100 Translational Medicine associated with TM4SF5

0 Patents (Medical) associated with TM4SF5

Literatures (Medical) associated with TM4SF5

01 Dec 2024·Life Sciences

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

Article

Author: 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.

01 Jan 2024·Cancer Communications

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

Article

Author: 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.

01 Sep 2023·iScience

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

Article

Author: 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.

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TM4SF5

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