1. Cell Biology
  2. Immunology and Inflammation
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Metabolic but not transcriptional regulation by PKM2 is important for Natural Killer cell responses

  1. Jessica F Walls
  2. Jeff J Subleski
  3. Erika M Palmieri
  4. Marieli Gonzalez Cotto
  5. Clair M Gardiner
  6. Daniel W McVicar
  7. David K Finlay  Is a corresponding author
  1. National Cancer Institute, United States
  2. Trinity College Dublin, Ireland
Research Article
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Cite this article as: eLife 2020;9:e59166 doi: 10.7554/eLife.59166

Abstract

Natural Killer (NK) cells have an important role in immune responses to viruses and tumours. Integrating changes in signal transduction pathways and cellular metabolism is essential for effective NK cells responses. The glycolytic enzyme Pyruvate Kinase Muscle 2 (PKM2) has described roles in regulating glycolytic flux and signal transduction, particularly gene transcription. While PKM2 expression is robustly induced in activated NK cells, mice lacking PKM2 in NK cells showed no defect in NK cell metabolism, transcription or anti-viral responses to MCMV infection. NK cell metabolism was maintained due to compensatory PKM1 expression in PKM2-null NK cells. To further investigate the role of PKM2 we used TEPP-46, which increases PKM2 catalytic activity while inhibiting any PKM2 signalling functions. NK cells activated with TEPP-46 had reduced effector function due to TEPP-46-induced increases in oxidative stress. Overall, PKM2-regulated glycolytic metabolism and redox status, not transcriptional control, facilitate optimal NK cells responses.

Article and author information

Author details

  1. Jessica F Walls

    Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jeff J Subleski

    Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Erika M Palmieri

    Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Marieli Gonzalez Cotto

    Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Clair M Gardiner

    School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  6. Daniel W McVicar

    Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. David K Finlay

    School of Biochemistry and Immunology and School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland
    For correspondence
    finlayd@tcd.ie
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2716-6679

Funding

National Institutes of Health

  • Daniel W McVicar

Wellcome (106811/Z/15/Z)

  • Jessica F Walls

National Institutes of Health

  • Jessica F Walls

National Institutes of Health

  • Erika M Palmieri

National Institutes of Health

  • Marieli Gonzalez Cotto

National Institutes of Health

  • Jeff J Subleski

Science Foundation Ireland (18/ERCS/6005)

  • David K Finlay

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

Ethics

Animal experimentation: Mice utilised in Ireland were maintained in compliance with Irish Department of Health and Children regulations and with the approval of the University of Dublin's ethical review board. Mice utilised in the USA were maintained in accordance with institutional guidelines for animal care and use at NCI Frederick, NIH.

Reviewing Editor

  1. Tiffany Horng, ShanghaiTech University, China

Publication history

  1. Received: May 21, 2020
  2. Accepted: August 15, 2020
  3. Accepted Manuscript published: August 19, 2020 (version 1)
  4. Version of Record published: September 2, 2020 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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