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Functional characterization of variants in human ABCC11, an axillary osmidrosis risk factor

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Abstract

Human ATP-binding cassette transporter C11 (ABCC11) is a membrane protein exhibiting ATP-dependent transport activity for a variety of lipophilic anions including endogenous substances and xenobiotics such as anti-cancer agents. Accumulating evidence indicates that ABCC11 wild type is responsible for the high-secretion phenotypes in human apocrine glands including wet type of earwax and the risk of axillary osmidrosis. Also, a less-functional variant of ABCC11 was reportedly associated with a risk for drug-induced toxicity in humans. Thus, functional change in ABCC11 may affect individual’s constitution and drug toxicity, which led us to reason that functional validation of genetic variations in ABCC11 should be of importance. Therefore, in addition to p.G180R (a well-characterized non-functional variant of ABCC11), we studied cellular expression and function of 10 variants of ABCC11. In this study, ABCC11 function was evaluated as an ATP-dependent transport of radio labeled-dehydroepiandrosterone sulfate using ABCC11-expressing plasma membrane vesicles. Except for p.G180R, other 10 variants were maturated as an N-linked glycoprotein and expressed on the plasma membrane. We found that six variants impaired the net cellular function of ABCC11. Among them, p.R630W was most influential. Including this identification of a significantly-dysfunctional variant, our findings will extend our understanding of genetic variations and biochemical features of ABCC11 protein.

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Acknowledgements

The authors thank Dr. Toshihisa Ishikawa for his continuous encouragement for this study and for kindly providing the expression vectors for some ABCC11 variants as well as Dr. Hiroshi Suzuki for his support. YT is an Excellent Young Researcher in MEXT Leading Initiative for Excellent Young Researchers.

Funding

This study was supported by JSPS KAKENHI Grant Numbers 15H05610, 19K16441, and 21H03350 (to YT).

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Authors and Affiliations

  1. Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Yu Toyoda & Tappei Takada

  2. Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan

    Yu Toyoda & Hirotaka Matsuo

Authors
  1. Yu Toyoda
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  2. Hirotaka Matsuo
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Contributions

Conceptualization: Yu Toyoda; methodology: Yu Toyoda; resources: Yu Toyoda; validation: Yu Toyoda; formal analysis: Yu Toyoda; investigation: Yu Toyoda; writing—original draft preparation: Yu Toyoda; writing—review and editing: Yu Toyoda, Hirotaka Matsuo, and Takada Tappei; supervision: Takada Tappei; project administration: Yu Toyoda; funding acquisition: Yu Toyoda; all authors read and approved the final manuscript.

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Correspondence to Yu Toyoda.

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Toyoda, Y., Matsuo, H. & Takada, T. Functional characterization of variants in human ABCC11, an axillary osmidrosis risk factor. Human Cell (2024). https://doi.org/10.1007/s13577-024-01074-x

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  • DOI: https://doi.org/10.1007/s13577-024-01074-x

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