Mammalian monocarboxylate transporter 7 (MCT7/Slc16a6) is a novel facilitative taurine transporter

Kei Higuchi,Koki Sugiyama,Ryuto Tomabechi,Hisanao Kishimoto,Katsuhisa Inoue

doi:10.1016/j.jbc.2022.101800

Kei Higuchi, Koki Sugiyama + Show 3 more

Open Access

https://doi.org/10.1016/j.jbc.2022.101800

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Abstract

Monocarboxylate transporter 7 (MCT7) is an orphan transporter expressed in the liver, brain, and in several types of cancer cells. It has also been reported to be a survival factor in melanoma and breast cancers. However, this survival mechanism is not yet fully understood due to MCT7’s unidentified substrate(s). Therefore, here we sought to identify MCT7 substrate(s) and characterize the transport mechanisms by analyzing amino acid transport in HEK293T cells and polarized Caco-2 cells. Analysis of amino acids revealed significant rapid reduction in taurine from cells transfected with enhanced green fluorescent protein-tagged MCT7. We found that taurine uptake and efflux by MCT7 was pH-independent and that the uptake was not saturated in the presence of taurine excess of 200 mM. Furthermore, we found that monocarboxylates and acidic amino acids inhibited MCT7-mediated taurine uptake. These results imply that MCT7 may be a low-affinity facilitative taurine transporter. We also found that MCT7 was localized at the basolateral membrane in polarized Caco-2 cells and that the induction of MCT7 expression in polarized Caco-2 cells enhanced taurine permeation. Finally, we demonstrated that interactions of MCT7 with ancillary proteins basigin/CD147 and embigin/GP70 enhanced MCT7-mediated taurine transport. In summary, these findings reveal that taurine is a novel substrate of MCT7 and that MCT7-mediated taurine transport might contribute to the efflux of taurine from cells.

Highlights

Prototypical monocarboxylate transporters (MCTs), other members transport monocarboxylates and zwitterionic metabolites as substrates
Monocarboxylate transporter 7 (MCT7) is highly expressed in melanoma cells, and single nucleotide polymorphisms are related to cutaneous melanoma survival [12]
In comparison to the other amino acids, only taurine content showed a significant decrease in MCT7-transfected cells, whereas not in mock-transfected cells

Summary

Introduction

Prototypical MCTs, other members transport monocarboxylates and zwitterionic metabolites as substrates. MCT9/SLC16A9 functions as a H+-independent carnitine efflux transporter [8]. The substrates of several MCTs have not been identified, and the physiological role has not been fully understood. Mammalian monocarboxylate transporter 7 (MCT7/ SLC16A6) is an orphan transporter of the SLC16A family whose substrates and transport mechanisms are yet to be characterized. An ortholog of mammalian MCT7 in zebrafish (encoded by Slc16a6a) is reported to transport a ketone body, β-hydroxybutyrate, and the loss of gene function was shown to cause steatosis of the liver [9]. Considering that ketogenesis occurs primarily in the mitochondria of hepatocytes, such wide expression of MCT7 implies multiple physiological roles in the body. Identification of mammalian MCT7 substrate(s) is crucial in understanding functionality. The purpose of this study was to identify MCT7 substrates and characterize transport mechanisms. MCT7 regulation by ancillary proteins CD147 and GP70 was investigated

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