Metabolic but not transcriptional regulation by PKM2 is important for Natural Killer cell responses
- National Cancer Institute, United States
- Trinity College Dublin, Ireland
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.
Data availability
RNA sequencing data has been uploaded to GEO (GSE156064).
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Total RNA sequencing of cultured splenic PKM2WT and PKM2KO NK cellsNCBI Gene Expression Omnibus, GSE156064.
Article and author information
Author details
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.
Reviewing Editor
- Tiffany Horng, ShanghaiTech University, China
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.
Version history
- Received: May 21, 2020
- Accepted: August 15, 2020
- Accepted Manuscript published: August 19, 2020 (version 1)
- 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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Metabolic but not transcriptional regulation by PKM2 is important for Natural Killer cell responses
eLife 9:e59166.
https://doi.org/10.7554/eLife.59166
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