Metabolic mapping of the entire human solute carrier superfamily

Solute carrier (SLC) transporters govern most of the chemical exchange across cellular membranes and are integral to metabolic regulation, which in turn is linked to cellular function and identity. Despite their key role, individual functions of the SLC superfamily members were not evaluated systematically. We determined the metabolic and transcriptional profiles upon SLC overexpression in knock-out or wild-type isogenic cell backgrounds for 378 SLCs and 441 SLCs, respectively. Targeted metabolomics provided a fingerprint of 189 intracellular metabolites, while transcriptomics offered insights into cellular programs modulated by SLC expression. Beyond the metabolic profiles of 102 SLCs directly related to their known substrates, we identified putative substrates or metabolic pathway connections for 71 SLCs without previously annotated bona fide substrates, including SLC45A4 as a new polyamine transporter. By comparing the molecular profiles, we identified functionally related SLC groups, including some with distinct impacts on osmolyte balancing and glycosylation. The assessment of functionally related human genes presented here may serve as a blueprint for other systematic studies and supports future investigations into the functional roles of SLCs.

溶质载体（Solute carrier, SLC）转运蛋白介导了绝大多数跨细胞膜的化学物质交换，是代谢调控的核心组成部分，而代谢调控又与细胞功能及细胞身份密切相关。尽管这类蛋白发挥着关键作用，但目前尚未对SLC超家族各成员的单独功能开展系统性评估。我们分别针对378种SLC在基因敲除型同基因细胞背景、441种SLC在野生型同基因细胞背景中开展过表达实验，以此测定对应的代谢组与转录组特征。靶向代谢组学为189种细胞内代谢物构建了特征指纹谱，而转录组学则揭示了SLC表达所调控的细胞程序相关信息。在与已知底物直接相关的102种SLC的代谢谱基础上，我们还为71种此前未被正式注释存在天然底物的SLC鉴定出了推定底物或代谢通路关联，其中包括作为新型多胺转运蛋白的SLC45A4。通过比对这些分子特征谱，我们鉴定出了功能相关的SLC家族群组，其中部分群组对渗透压平衡调节和糖基化过程具有显著调控作用。本研究呈现的针对人类功能相关基因的系统性评估，可为其他同类系统性研究提供参考范式，同时也为后续探究SLC的功能角色提供有力支撑。