8.A.75 The Transmembrane 4 L6 (TM4L6) Family 

The human TransMembrane 4 L6 (TM4L6) protein (8.A.75.1.1)  interacts directly with the thiamin uptake porter, hTHTR-2 (2.A.48.1.4). These two proteins display overlap in intracellular vesicles and at the cell membrane. Co-expression of hTHTR-2 with TM4SF4 led to a significant induction in thiamine uptake, while silencing of TM4SF4 with gene-specific siRNA led to a significant decrease in thiamine uptake.  Thus, TM4SF4 behaves like an activator of hTHTR-2 (Subramanian et al. 2014).The L6 domain tetarspanin TM4SF4 also regluates endocine pancreas differentiation and directed cell migration (Anderson et al. 2011).  It is overexpressed in hepatic cancers and plays a role in promotion of cancer cell proliferation (Li et al. 2012).  This family is the PF05805 family of Pfam with domain L6_membrane.

TM4SF20 (8.A.27.1.4) is a 4 TMS protein that inhibits regulated intramembrane proteolysis of CREB3L1, inhibiting its activation and the induction of collagen synthesis (Chen et al. 2014; Chen et al. 2016). Ceramide alters (inverts) the TM4SF20 membrane topology (Chen et al. 2016) and reverses the direction through which transmembrane helices are translocated into the endoplasmic reticulum membrane during translation of TM4SF20.



Anderson, K.R., R.A. Singer, D.A. Balderes, L. Hernandez-Lagunas, C.W. Johnson, K.B. Artinger, and L. Sussel. (2011). The L6 domain tetraspanin Tm4sf4 regulates endocrine pancreas differentiation and directed cell migration. Development 138: 3213-3224.

Attwood, M.M., A. Krishnan, V. Pivotti, S. Yazdi, M.S. Almén, and H.B. Schiöth. (2016). Topology based identification and comprehensive classification of four-transmembrane helix containing proteins (4TMs) in the human genome. BMC Genomics 17: 268.

Cai, L., Z. Liao, S. Li, R. Wu, J. Li, F. Ren, and H. Zhang. (2022). PLP1 may serve as a potential diagnostic biomarker of uterine fibroids. Front Genet 13: 1045395.

Chen, Q., B. Denard, C.E. Lee, S. Han, J.S. Ye, and J. Ye. (2016). Inverting the Topology of a Transmembrane Protein by Regulating the Translocation of the First Transmembrane Helix. Mol. Cell 63: 567-578.

Chen, Q., C.E. Lee, B. Denard, and J. Ye. (2014). Sustained induction of collagen synthesis by TGF-β requires regulated intramembrane proteolysis of CREB3L1. PLoS One 9: e108528.

Choi, S.I., S.Y. Kim, J. Lee, E.W. Cho, and I.G. Kim. (2014). TM4SF4 overexpression in radiation-resistant lung carcinoma cells activates IGF1R via elevation of IGF1. Oncotarget 5: 9823-9837.

Hong, J., B. Wong, C. Huynh, B. Tang, G. Ruffenach, M. Li, S. Umar, X. Yang, and M. Eghbali. (2023). -marked Endothelial Subpopulation Is Dysregulated in Pulmonary Arterial Hypertension. Am J Respir Cell Mol Biol 68: 381-394.

Jung, J.W., J.E. Kim, E. Kim, and J.W. Lee. (2020). Amino acid transporters as tetraspanin TM4SF5 binding partners. Exp Mol Med 52: 7-14.

Jung, J.W., J.E. Kim, E. Kim, H. Lee, H. Lee, E.A. Shin, and J.W. Lee. (2022). Liver-originated small extracellular vesicles with TM4SF5 target brown adipose tissue for homeostatic glucose clearance. J Extracell Vesicles 11: e12262.

Jung, J.W., S.J.Y. Macalino, M. Cui, J.E. Kim, H.J. Kim, D.G. Song, S.H. Nam, S. Kim, S. Choi, and J.W. Lee. (2019). Transmembrane 4 L Six Family Member 5 Senses Arginine for mTORC1 Signaling. Cell Metab. [Epub: Ahead of Print]

Kim, J.E., E. Kim, and J.W. Lee. (2022). TM4SF5-Mediated Regulation of Hepatocyte Transporters during Metabolic Liver Diseases. Int J Mol Sci 23:.

Kim, J.E., S.Y. Park, C. Kwak, Y. Lee, D.G. Song, J.W. Jung, H. Lee, E.A. Shin, Y. Pinanga, K.H. Pyo, E.H. Lee, W. Kim, S. Kim, C.D. Jun, J. Yun, S. Choi, H.W. Rhee, K.H. Liu, and J.W. Lee. (2024). Glucose-mediated mitochondrial reprogramming by cholesterol export at TM4SF5-enriched mitochondria-lysosome contact sites. Cancer Commun (Lond) 44: 47-75.

Lee, H., E. Kim, E.A. Shin, J.C. Shon, H. Sun, J.E. Kim, J.W. Jung, H. Lee, Y. Pinanga, D.G. Song, K.H. Liu, and J.W. Lee. (2022). Crosstalk between TM4SF5 and GLUT8 regulates fructose metabolism in hepatic steatosis. Mol Metab 58: 101451.

Li, Y., L. Wang, J. Qiu, L. Da, P. Tiollais, Z. Li, and M. Zhao. (2012). Human tetraspanin transmembrane 4 superfamily member 4 or intestinal and liver tetraspan membrane protein is overexpressed in hepatocellular carcinoma and accelerates tumor cell growth. Acta Biochim Biophys Sin (Shanghai) 44: 224-232.

Park, D., E. Kim, H. Lee, E.A. Shin, H. Lee, and J.W. Lee. (2021). Tetraspanin TM4SF5 in hepatocytes negatively modulates SLC27A transporters during acute fatty acid supply. Arch Biochem Biophys 710: 109004.

Rossi, G., G. Ordazzo, N.N. Vanni, V. Castoldi, A. Iannielli, D. Di Silvestre, E. Bellini, L. Bernardo, S.G. Giannelli, M. Luoni, S. Muggeo, L. Leocani, P. Mauri, and V. Broccoli. (2023). MCT1-dependent energetic failure and neuroinflammation underlie optic nerve degeneration in Wolfram syndrome mice. Elife 12:.

Subramanian, V.S., S.M. Nabokina, and H.M. Said. (2014). Association of TM4SF4 with the human thiamine transporter-2 in intestinal epithelial cells. Dig Dis Sci 59: 583-590.

Wang, J., L.N. Kinch, B. Denard, C.E. Lee, E. Esmaeilzadeh Gharehdaghi, N. Grishin, and J. Ye. (2019). Identification of residues critical for topology inversion of the transmembrane protein TM4SF20 through regulated alternative translocation. J. Biol. Chem. 294: 6054-6061.

Ye, J. (2020). Transcription factors activated through RIP (Regulated Intramembrane Proteolysis) and RAT (Regulated Alternative Translocation)). J. Biol. Chem. [Epub: Ahead of Print]

Zhao, J., C. Wang, R. Fan, X. Liu, and W. Zhang. (2022). A prognostic model based on clusters of molecules related to epithelial-mesenchymal transition for idiopathic pulmonary fibrosis. Front Genet 13: 1109903.

Zheng, Y.W., M. Wang, Z.M. Zhong, G.Q. Wu, T. Zhang, L.L. Chen, and M. Li. (2022). TM4SF1 promotes glioma malignancy through multiple mechanisms. Neoplasma 69: 859-867.


TC#NameOrganismal TypeExample

The TM4 L6 member 4 protein, TM4L6 of 202 aas and 4 TMSs.  Functions as an activator of the thiamin uptake porter, ThTr2 (Subramanian et al. 2014) as well as liver, lung and pancreatic cancers (Li et al. 2012; Choi et al. 2014; Anderson et al. 2011).

TM4SF4 of Homo sapiens


TM4SF18 of 201 aas and 4 TMSs (Attwood et al. 2016).

TM4SF18 of Homo sapiens


TM4SF19 of 209 aas and 4 TMSs.  Also called Osteoclast maturation-associated gene 4 protein and Tetraspan membrane protein OCTM4

TM4SF19 of Homo sapiens


Transmembrane 4 L6 family member 20, TM4SF20, of 229 aas and 4 TMSs in a 3 + 1 TMS arrangement.  Ceramide regulates TM4SF20 through topological inversion by altering the direction through which the protein is translocated across membranes during translation. This regulatory mechanism, denoted regulated alternative translocation, depends on a GXXXN motif present in the first TMS of TM4SF20, and residues important for this inversion have been identified (Wang et al. 2019; Ye 2020).

TM4SF20 of Homo sapiens


Transmembrane 4 L6 family member 5 of 197 aas and 4 TMSs, TM4SF5 It is also called Tetraspan transmembrane protein L6H. Lysosomal TM4SF5 senses and enables arginine efflux for mTORC1/S6K1 activation (Jung et al. 2019). TM4SF5 can be N-glycosylated and palmitoylated, enabling homophilic or heterophilic binding to diverse membrane proteins and receptors, including growth factor receptors, integrins, and tetraspanins. It promotes protein-protein complexes for the spatiotemporal regulation of the expression, stability, binding, and signaling activity of its binding partners (Jung et al. 2020). 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. 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. Diverse amino acid transporters are precipitated with TM4SF5 (Jung et al. 2020). Tetraspanin TM4SF5 in hepatocytes negatively modulates SLC27A transporters during acute fatty acid supply (Park et al. 2021). Hepatic TM4SF5 modulates GLUT8 localization and activity through transient binding, leading to steatosis-related fructose uptake and lipogenesis. Thus, TM4SF5 and/or GLUT8 may be promising treatment targets against liver steatosis resulting from excessive fructose consumption (Lee et al. 2022). TM4SF5 interacts with and regulates many solute transporters for amino acids and sugars, and these may be indicative of liver diseases (Kim et al. 2022). Liver-originated small extracellular vesicles with TM4SF5 target brown adipose tissue for homeostatic glucose clearance (Jung et al. 2022).  Glucose mediates mitochondrial reprogramming by cholesterol export at TM4SF5-enriched mitochondria-lysosome contact sites (Kim et al. 2024).


TM4SF5 of Homo sapiens


Transmembrane 4 L6 family member 1, TM4SF1 or TM4L6 family member 1 or CM3S1, of 202 aas and 4 TMSs in a 3 + 1 TMS arrangement. TM4SF1 is highly expressed in glioma tumor tissues and cell lines. The expression levels of TM4SF1 were negatively correlated with patients' survival rates. Silencing TM4SF1 by RNA interference inhibited the proliferation, migration, and invasion of glioma cells. Moreover, TM4SF1 silencing induced glioma cell cycle arrest and early apoptosis, while overexpression of TM4SF1 in glioma cells exhibited the opposite effects. Loss of TM4SF1 reduced phospho-ATK, Cyclin D1, Bcl-2, and MMP-9 levels in glioma cells. These findings provide novel insights into glioma pathogenesis (Zheng et al. 2022). The TM4SF1 encoding gene may be upregulated in uterine fibrosis (Cai et al. 2022). Six epithelial- mesenchymal transition-related genes, including TM4SF1, provide bioinformatic guidance to identify prognostic markers for idiopathic pulmonary fibrosis (Zhao et al. 2022). Reduction of MCT1 and its partner basigin are highly enriched in retinal glia and myelin-forming oligodendrocytes in optic nerves together with wolframin. Loss of MCT1 causes a failure in lactate transfer from glial to neuronal cell bodies and axons, leading to a chronic hypometabolic state in mice (Rossi et al. 2023).  A Tm4sf1-marked endothelial subpopulation is dysregulated in pulmonary arterial hypertension (Hong et al. 2023).

TM4SF1 of Homo sapiens