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).
-
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.
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
- Tiffany Horng, ShanghaiTech University, China
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.
Metrics
-
- 3,030
- Page views
-
- 398
- Downloads
-
- 16
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Metabolic but not transcriptional regulation by PKM2 is important for Natural Killer cell responses
eLife 9:e59166.
https://doi.org/10.7554/eLife.59166
Further reading
-
- Cell Biology
- Structural Biology and Molecular Biophysics
Previously we showed that 2D template matching (2DTM) can be used to localize macromolecular complexes in images recorded by cryogenic electron microscopy (cryo-EM) with high precision, even in the presence of noise and cellular background (Lucas et al., 2021; Lucas et al., 2022). Here, we show that once localized, these particles may be averaged together to generate high-resolution 3D reconstructions. However, regions included in the template may suffer from template bias, leading to inflated resolution estimates and making the interpretation of high-resolution features unreliable. We evaluate conditions that minimize template bias while retaining the benefits of high-precision localization, and we show that molecular features not present in the template can be reconstructed at high resolution from targets found by 2DTM, extending prior work at low-resolution. Moreover, we present a quantitative metric for template bias to aid the interpretation of 3D reconstructions calculated with particles localized using high-resolution templates and fine angular sampling.
-
- Cell Biology
- Immunology and Inflammation
Dendritic cells (DCs), the key antigen-presenting cells, are primary regulators of immune responses. Transcriptional regulation of DC development had been one of the major research interests in DC biology, however, the epigenetic regulatory mechanisms during DC development remains unclear. Here, we report that Histone deacetylase 3 (Hdac3), an important epigenetic regulator, is highly expressed in pDCs, and its deficiency profoundly impaired the development of pDCs. Significant disturbance of homeostasis of hematopoietic progenitors was also observed in HDAC3-deficient mice, manifested by altered cell numbers of these progenitors and defective differentiation potentials for pDCs. Using the in vitro Flt3L supplemented DC culture system, we further demonstrated that HDAC3 was required for the differentiation of pDCs from progenitors at all developmental stages. Mechanistically, HDAC3 deficiency resulted in enhanced expression of cDC1-associated genes, owing to markedly elevated H3K27 acetylation (H3K27ac) at these gene sites in BM pDCs. In contrast, the expression of pDC-associated genes was significantly downregulated, leading to defective pDC differentiation.
