Illuminating the function of the orphan transporter, SLC22A10, in humans and other primates

Authors: YEE, SOOK WAH - University Of California San Francisco (UCSF); FERRÁNDEZ-PERAL, LUIS - Pompeu Fabra University; ALENTORN-MORON, POL - Pompeu Fabra University; FONTSERE, CLAUDIA - Pompeu Fabra University; CEYLAN, MERVE - Uppsala University; KOLESKE, MEGAN - University Of California San Francisco (UCSF); HANDIN, NIKLAS - Uppsala University; Artegoitia Etchev, Virginia; LARA, GIOVANNI - University Of California San Francisco (UCSF); CHIEN, HUAN-CHIEH - University Of California San Francisco (UCSF); ZHOU, XUJIA - University Of California San Francisco (UCSF); DAINAT, JACQUES - Uppsala University; ZALEVSKY, ARTHUR - University Of California San Francisco (UCSF); SALI, ANDREJ - University Of California San Francisco (UCSF); BRAND, COLIN - University Of California San Francisco (UCSF); WOLFREYS, FINN - University Of California San Francisco (UCSF); YANG, JIA - University Of California San Francisco (UCSF); GESTWICKI, JASON - University Of California San Francisco (UCSF); CAPRA, JOHN - University Of California San Francisco (UCSF); ARTURSSON, PER - Uppsala University; Newman, John; MARQUÈS-BONET, TOMÀS - Pompeu Fabra University; GIACOMINI, KATHLEEN - University Of California San Francisco (UCSF)

Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/6/2024
Publication Date: 5/23/2024
Citation: Yee, S., Ferrández-Peral, L., Alentorn-Moron, P., Fontsere, C., Ceylan, M., Koleske, M.L., Handin, N., Artegoitia Etchev, V.M., Lara, G., Chien, H., Zhou, X., Dainat, J., Zalevsky, A., Sali, A., Brand, C.M., Wolfreys, F.D., Yang, J., Gestwicki, J.E., Capra, J.A., Artursson, P., Newman, J.W., Marquès-Bonet, T., Giacomini, K.M. 2024. Illuminating the function of the orphan transporter, SLC22A10, in humans and other primates. Nature Communications. 15. Article 4380. https://doi.org/10.1038/s41467-024-48569-7.
DOI: https://doi.org/10.1038/s41467-024-48569-7

Interpretive Summary: The solute carrier family 22 member 10 (SLC22A10) is classified as a membrane transport protein but its substrates and function are currently unknown. Here we describe the substrate specificity and functional characteristics of SLC22A10 from multiple hominid species. In cell culture systems, the human SLC22A10 tagged with green fluorescent protein was not found in the plasma membrane, while great ape SLC22A10 orthologs were. Estradiol-17ß-glucuronide accumulated over 4-fold in cells expressing great ape SLC22A10 orthologs but the human SLC22A10 displayed no uptake function. Protein amino acid sequence alignments revealed two amino acid differences including a proline vs leucine at position 220 of the human vs great ape SLC22A10s. Site-directed mutagenesis replacing proline 220 with leucine yielded the human SLC22A10-P220L, a protein with excellent plasma membrane localization and associated uptake function. Neanderthal and Denisovan genomes also indicate human-like sequences at proline 220, corroborating that SLC22A10 were rendered nonfunctional during hominin evolution after diverging from our common ancestor with the chimpanzee. These findings demonstrate that human SLC22A10 does not function as a plasma membrane transporter, whereas orthologs in great apes transport sex steroid conjugates.

Technical Abstract: SLC22A10 is classified as an orphan transporter with unknown substrates and function. Here we describe the discovery of the substrate specificity and functional characteristics of SLC22A10. The human SLC22A10 tagged with green fluorescent protein was found to be absent from the plasma membrane, in contrast to the SLC22A10 orthologs found in great apes. Estradiol-17ß-glucuronide accumulated in cells expressing great ape SLC22A10 orthologs (over 4-fold, p<0.001). In contrast, human SLC22A10 displayed no uptake function. Sequence alignments revealed two amino acid differences including a proline at position 220 of the human SLC22A10 and a leucine at the same position of great ape orthologs. Site-directed mutagenesis yielding the human SLC22A10-P220L produced a protein with excellent plasma membrane localization and associated uptake function. Neanderthal and Denisovan genomes show human-like sequences at proline 220 position, corroborating that SLC22A10 were rendered nonfunctional during hominin evolution after our common ancestor with the chimpanzee. These findings demonstrate that human SLC22A10 does not function as a plasma membrane transporter, whereas orthologs in great apes transport sex steroid conjugates.