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Cited by 4Drug Transport and Resistance MechanismsPharmacogenetics and Drug MetabolismEstrogen and related hormone effects

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

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Yee, Sook Wah, Ferrández-Peral, Luis, Alentorn-Moron, Pol, Fontsere, Claudia, Ceylan, Merve, Koleske, Megan L., Handin, Niklas, Artegoitia, Virginia M., Lara, Giovanni, Chien, Huan-Chieh, Zhou, Xujia, Dainat, Jacques, Zalevsky, Arthur, Sali, Andrej, Brand, Colin M., Wolfreys, Finn D., Yang, Jia, Gestwicki, Jason E., Capra, John A., Artursson, Per, Newman, John W., Marquès-Bonet, Tomàs, Giacomini, Kathleen M.·2024·Nature Communications
DOI 10.1038/s41467-024-48569-7PMC PMC11116522

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Abstract

SLC22A10 is an orphan transporter with unknown substrates and function. The goal of this study is to elucidate its substrate specificity and functional characteristics. In contrast to orthologs from great apes, human SLC22A10, tagged with green fluorescent protein, is not expressed on the plasma membrane. Cells expressing great ape SLC22A10 orthologs exhibit significant accumulation of estradiol-17β-glucuronide, unlike those expressing human SLC22A10. Sequence alignments reveal a proline at position 220 in humans, which is a leucine in great apes. Replacing proline with leucine in SLC22A10-P220L restores plasma membrane localization and uptake function. Neanderthal and Denisovan genomes show proline at position 220, akin to modern humans, indicating functional loss during hominin evolution. Human SLC22A10 is a unitary pseudogene due to a fixed missense mutation, P220, while in great apes, its orthologs transport sex steroid conjugates. Characterizing SLC22A10 across species sheds light on its biological role, influencing organism development and steroid homeostasis.

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Metadata

Authors
Yee, S. W., Ferrández-Peral, L., Alentorn-Moron, P., Fontsere, C., Ceylan, M., Koleske, M. L., Handin, N., Artegoitia, V. M., Lara, G., Chien, H.-C., 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.
Affiliations
  • University of California, San Francisco (US)
  • Barcelona Biomedical Research Park (ES)
  • University of Copenhagen (DK)
  • Uppsala University (SE)
  • Agricultural Research Service (US)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
Giacomini, Kathleen M.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-05-23
Volume
15
Issue
1
Pages
4380-4380
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-48569-7
PMC
PMC11116522
OpenAlex
W4398239022
Cited by
4
References
8
Citations by year
2026: 1 · 2025: 3
FWCI
0.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • HAL (submittedVersion, cc-by)
  • Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • Uppsala University Publications (Uppsala University) (submittedVersion, other-oa)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (GM139875, GM117163)
  • U.S. Department of Health & Human Services | NIH | National Eye Institute (EY032161)
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
Keywords
orphan transporter, estradiol-17β-glucuronide, substrate specificity, plasma membrane localization, Neanderthal genome, hominin evolution, pseudogenes, missense mutations, primate comparative genomics
MeSH terms
Amino Acid Sequence, Animals, Estradiol, Humans, Primates, Pseudogenes, Substrate Specificity, Hominidae, Mutation, Missense, Organic Anion Transporters, Organic Cation Transport Proteins, HEK293 Cells

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