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Amino Acid Transporters As Tetraspanin TM4SF5 Binding Partners Jae Woo Jung1,Jieonkim2,Eunmikim2 and Jung Weon Lee 1,2

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Amino Acid Transporters As Tetraspanin TM4SF5 Binding Partners Jae Woo Jung1,Jieonkim2,Eunmikim2 and Jung Weon Lee 1,2 Jung et al. Experimental & Molecular Medicine (2020) 52:7–14 https://doi.org/10.1038/s12276-019-0363-7 Experimental & Molecular Medicine REVIEW ARTICLE Open Access Amino acid transporters as tetraspanin TM4SF5 binding partners Jae Woo Jung1,JiEonKim2,EunmiKim2 and Jung Weon Lee 1,2 Abstract Transmembrane 4 L6 family member 5 (TM4SF5) is a tetraspanin that has four transmembrane domains and can be N- glycosylated and palmitoylated. These posttranslational modifications of TM4SF5 enable homophilic or heterophilic binding to diverse membrane proteins and receptors, including growth factor receptors, integrins, and tetraspanins. As a member of the tetraspanin family, TM4SF5 promotes protein-protein complexes for the spatiotemporal regulation of the expression, stability, binding, and signaling activity of its binding partners. Chronic diseases such as liver diseases involve bidirectional communication between extracellular and intracellular spaces, resulting in immune-related metabolic effects during the development of pathological phenotypes. It has recently been shown that, during the development of fibrosis and cancer, TM4SF5 forms protein-protein complexes with amino acid transporters, which can lead to the regulation of cystine uptake from the extracellular space to the cytosol and arginine export from the lysosomal lumen to the cytosol. Furthermore, using proteomic analyses, we found that diverse amino acid transporters were precipitated with TM4SF5, although these binding partners need to be confirmed by other approaches and in functionally relevant studies. This review discusses the scope of the pathological relevance of TM4SF5 and its binding to certain amino acid transporters. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction on the plasma membrane and the mitochondria, lyso- Importing and exporting biological matter in and out of some, and other intracellular organelles. SLCs transport a cell are fundamental and integral processes for home- small molecules, and inorganic and organic ions2,3, such ostasis and survival. In the same context, membrane as sugars (SLC2, 5, 45, 50, and 60)4, amino acids (SLC1, 3, – transporters are core proteins that govern cell status and 7, 17, 32, 36, 38, and 43)5 9, fatty acids (SLC27)10, calcium – fate, and it is not surprising that ~10% of the genome (SLC8, 24, and 64)11 13, zinc (SLC30 and 39)14,15, and encodes transporter and transporter-related genes1. many others. The lists and functions of SLCs are well Solute carrier transporter families (SLCs) are the second summarized on the Bioparadigms webpage (https://www. largest family of membrane proteins, consisting of 52 bioparadigms.org/slc/intro.htm). The topology and families with almost 400 transporters. SLCs are composed structure vary among transporters, which are generally of various transporters with different modes of transport, composed of a number of hydrophobic helices connected including ion couplers, exchangers, and passive trans- with loops. Some SLCs exist as heterodimers (SLC3A2 porters. SLCs are ubiquitously expressed in almost all with SLC7A5-8, 10–11), and others exist as monomers. human cells, and their intracellular localizations are found Amino acid transporters in disease SLCs transport molecules fundamental for homeostatic Correspondence: Jung Weon Lee ([email protected]) survival and growth such that mutations and either 1Interdisciplinary Program in Genetic Engineering, Seoul National University, enhancing or attenuating malfunctions of SLCs can cause Seoul 08826, Republic of Korea diseases. Approximately 20% of human SLC mutations are 2Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea These authors contributed equally: Jae Woo Jung, Ji Eon Kim, Eunmi Kim © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Korean Society for Biochemistry and Molecular Biology Jung et al. Experimental & Molecular Medicine (2020) 52:7–14 8 related to diseases, according to the Online Mendelian collagen network, which accounts for 30% of all proteins Inheritance in Man (OMIM) database16. in the organisms24. Collagens are generally produced by activated myofibroblasts24. Emerging consensus on the Amino acid transporters and inflammatory diseases sources of fibrogenic cells provides the rationale and Inflammation is a normal response to injury in the opportunity for investigating increasingly diverse ECM human body. This response requires immune cells to proteins in addition to collagens and different cell types, react to cellular damage, and this reaction includes infil- including epithelial cells, in addition to fibroblasts. We tration of and metabolic changes in immune cells and recently reported that activated myofibroblasts promote leads to the modification of cell fate and effector function. collagen expression, whereas epithelial cells induce lami- An arginine transporter, SLC7A2, was shown to play a nin expression, in vitro, upon activation of the pivotal role in inflammation-associated colon tumor- TGFβ1 signaling pathway and chemical induction of −/− igenesis17; the Slc7a2 mice serving as colon cancer fibrosis in animal tissues25,26. models were more susceptible to azoxymethane-dextran In addition, certain amino acid transporters have been sulfate sodium-induced switching of macrophages to the shown to be involved in fibrosis. Analysis of allergic air- M2 phenotype and activation. Levels of SLC15A1, a way inflammation and bleomycin-induced inflammation peptide transporter, were also increased by pro- in CAT2 (cationic amino acid transporter 2) deficient inflammatory cytokines in conjunction with increases in mice has shown that, although inflammation is indepen- tumor necrosis factor-α and interferon-γ, being involved dent of CAT2 expression, bleomycin-induced fibrosis is in inflammatory bowel disease (IBD)18. SLC22A genes dependent on CAT227. We have recently reported that a − were also shown to be high susceptibility genes for IBD cystine/glutamate antiporter, the xc system, is involved and to be located in a genetic location called IBD in the regulation of intracellular glutathione levels and locus 519. reactive oxygen species (ROS) levels during TM4SF5- mediated pulmonary fibrosis28 (see the below section for Amino acid transporters and liver diseases details). Because the liver is a central organ of metabolic homeostasis, malfunction(s) to the mechanism of external Amino acid transporters and cancer nutrient import into liver cells can lead to serious Cancer cells have some functions, such as continuous pathological diseases. Liver disease is chronic and devel- growth and proliferation, that require large amounts of ops in an inflammatory environment. Non-alcoholic fatty energy; therefore, cancer cells undergo metabolic change liver disease (NAFLD) is characterized by excessive lipid that results in rapid energy production. Sufficient energy accumulation in the liver and is often closely related to production is an important requirement for the survival obesity. Because excessive glucose can be stored in the and rapid growth of cancer cells. Glucose is a major form of lipids, it is logically related glucose transporters in energy source for cancer cells, and amino acids, lipids, and NAFLD. SLC2A1 (GLUT1), a high-affinity glucose other nutrients are imported from the extracellular transporter expressed ubiquitously, has been shown to be environment by many types of transporters found in the a susceptibility factor of NAFLD20; several single plasma membrane. The SLC family mainly transports nucleotide polymorphisms (SNPs) are also closely related nutrients with high affinity and specificity, but abnormal to NAFLD but not to type 2 diabetes. Trehalose, a SLC2 expression or regulation of SLCs can lead to poor prog- family inhibitor also known as a sugar inhibitor, has been noses of many cancers. The regulation of SLC expression shown to dramatically ameliorate NAFLD symptoms in and activation could therefore be a rate-limiting factor for mouse models by mimicking starvation to induce autop- tumor progression. The glucose-transporting proteins hagy21. Genetically ablating Slc7a3 in zebrafish, in which (GLUTs) in the SLC family are important in cancer it encodes a cationic amino acid transporter, results in development because of the Warburg effect. Otto War- defects in arginine-dependent nitric oxide synthesis, burg described the fate of glucose transported into cancer which leads to hepatic steatosis22. cells, indicating that cancer cells tend to undergo glyco- lysis, even in the presence of oxygen, instead of oxidative Amino acid transporters and fibrosis phosphorylation29. Glycolysis is less efficient
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