Amino acid transporters as tetraspanin TM4SF5 binding partners

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. Interactions between a membrane protein and transporters that move amino acids in and out of cells may play a prominent role in various diseases. The transmembrane protein TM4SF5 is known to regulate the activity of diverse signaling pathways, and has been linked to various liver diseases. Jung Weon Lee and colleagues at Seoul National University review the recently identified interplay between TM4SF5 and transporter proteins that regulate trafficking of the amino acids cysteine and arginine. Through its interactions with cysteine transporters, TM4SF5 appears to contribute to hormetic production of damaging chemicals that can cause the tissue scarring underlying idiopathic pulmonary fibrosis. Evidence also suggests that TM4SF5-facilitated arginine trafficking may contribute to liver cancer recurrence. This protein may also interact with other prominent transporters, and the authors conclude that TM4SF5 may affect other, still undefined pathological processes.