A surface proton antenna in carbonic anhydrase II supports lactate transport in cancer cells

Abstract

Many tumor cells produce vast amounts of lactate and acid, which have to be removed from the cell to avoid intracellular lactacidosis and suffocation of metabolism. In the present study, we show that proton-driven lactate flux is enhanced by the intracellular carbonic anhydrase CAII, which is colocalized with the monocarboxylate transporter MCT1 in MCF-7 breast cancer cells. Co-expression of MCTs with various CAII mutants in Xenopus oocytes demonstrated that CAII facilitates MCT transport activity via CAII-Glu69 and CAII-Asp72, which could function as surface proton antennae for the enzyme. While CAII-Glu69 and CAII-Asp72 seem to mediate proton transfer between enzyme and transporter, CAII-His64, the central residue of the enzyme's intramolecular proton shuttle, is not involved in proton shuttling between the two proteins, but mediates binding between MCT and CAII. Taken together, the results suggest that CAII features a moiety that exclusively mediates proton exchange with the MCT to facilitate transport activity.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1-9.

Article and author information

Author details

  1. Sina Ibne Noor

    Division of General Zoology, Department of Biology, University of Kaiserslautern, Kaiserslautern, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Somayeh Jamali

    Division of General Zoology, Department of Biology, University of Kaiserslautern, Kaiserslautern, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Samantha Ames

    Division of General Zoology, Department of Biology, University of Kaiserslautern, Kaiserslautern, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Silke Langer

    Division of General Zoology, Department of Biology, University of Kaiserslautern, Kaiserslautern, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Joachim W Deitmer

    Division of General Zoology, Department of Biology, University of Kaiserslautern, Kaiserslautern, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Holger M Becker

    Division of General Zoology, Department of Biology, University of Kaiserslautern, Kaiserslautern, Germany
    For correspondence
    Holger.Becker@tiho-hannover.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2700-6117

Funding

Deutsche Forschungsgemeinschaft (BE 4310/6-1)

  • Holger M Becker

Stiftung Rheinland-Pfalz für Innovation (961-386261/957)

  • Holger M Becker

Research Initiative BioComp

  • Joachim W Deitmer
  • Holger M Becker

Landesschwerpunkt Membrantransport

  • Joachim W Deitmer
  • Holger M Becker

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: The procedure of removing oocytes from Xenopus laevis females was approved by the Landesuntersuchungsamt Rheinland-Pfalz, Koblenz (23 177-07/A07-2-003 {section sign}6) and the Niedersächsisches Landesamt für Verbraucherschutz und Lebensmittelsicherheit, Oldenburg (33.19-42502-05-17A113).

Copyright

© 2018, Noor et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Sina Ibne Noor
  2. Somayeh Jamali
  3. Samantha Ames
  4. Silke Langer
  5. Joachim W Deitmer
  6. Holger M Becker
(2018)
A surface proton antenna in carbonic anhydrase II supports lactate transport in cancer cells
eLife 7:e35176.
https://doi.org/10.7554/eLife.35176

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https://doi.org/10.7554/eLife.35176

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