Fan Shih-Jung, Goberdhan Deborah C I
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
Front Pharmacol. 2018 Jun 19;9:640. doi: 10.3389/fphar.2018.00640. eCollection 2018.
Solute Carriers (SLCs) are involved in the transport of substances across lipid bilayers, including nutrients like amino acids. Amino acids increase the activity of the microenvironmental sensor mechanistic Target of Rapamycin Complex 1 (mTORC1) to promote cellular growth and anabolic processes. They can be brought in to cells by a wide range of SLCs including the closely related Proton-assisted Amino acid Transporter (PAT or SLC36) and Sodium-coupled Neutral Amino acid Transporter (SNAT or SLC38) families. More than a decade ago, the first evidence emerged that members of the PAT family can act as amino acid-stimulated receptors, or so-called "transceptors," connecting amino acids to mTORC1 activation. Since then, further studies in human cell models have suggested that other PAT and SNAT family members, which share significant homology within their transmembrane domains, can act as transceptors. A paradigm shift has also led to the PATs and SNATs at the surface of multiple intracellular compartments being linked to the recruitment and activation of different pools of mTORC1. Much focus has been on late endosomes and lysosomes as mTORC1 regulatory hubs, but more recently a Golgi-localized PAT was shown to be required for mTORC1 activation. PATs and SNATs can also traffic between the cell surface and intracellular compartments, with regulation of this movement providing a means of controlling their mTORC1 regulatory activity. These emerging features of PAT and SNAT amino acid sensors, including the transceptor mechanism, have implications for the pharmacological inhibition of mTORC1 and new therapeutic interventions.
溶质载体（SLCs）参与物质跨脂质双层的转运，包括氨基酸等营养物质。氨基酸可增强微环境传感器雷帕霉素复合物1（mTORC1）的活性，以促进细胞生长和合成代谢过程。多种SLCs可将氨基酸转运入细胞，包括关系密切的质子辅助氨基酸转运体（PAT或SLC36）和钠偶联中性氨基酸转运体（SNAT或SLC38）家族。十多年前，首次有证据表明PAT家族成员可作为氨基酸刺激受体，即所谓的“转ceptor”，将氨基酸与mTORC1激活联系起来。从那时起，在人类细胞模型中的进一步研究表明，其他PAT和SNAT家族成员在其跨膜结构域内具有显著同源性，也可作为转ceptor发挥作用。范式转变还导致多个细胞内区室表面的PATs和SNATs与不同池的mTORC1的募集和激活相关联。人们一直非常关注晚期内体和溶酶体作为mTORC1调节中心，但最近发现高尔基体定位的PAT是mTORC1激活所必需的。PATs和SNATs也可在细胞表面和细胞内区室之间运输，对这种运输的调节提供了一种控制其mTORC1调节活性的手段。PAT和SNAT氨基酸传感器的这些新出现的特征，包括转ceptor机制，对mTORC1的药理学抑制和新的治疗干预具有重要意义。
