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Reply to: GOT1 constrains TH17 cell differentiation, while promoting iTreg cell differentiation

Nature volume 614, pages E12–E14 (2023)Cite this article

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The Original Article was published on 01 February 2023

replying to W. Xu et al. Nature https://doi.org/10.1038/s41586-022-05602-3 (2023)

In their study2, in vitro differentiation into TH17 cells of T cells from mice with a chronic deletion of Got1 using Cd4-cre (Cre begins to function during the double-positive stage of T cell development in the thymus) showed slightly increased levels of IL-17+ cells, and slightly decreased levels of FOXP3+ cells. However, in two separate experiments by W. Xu et al.2 using mice with EAE, careful analysis seems to suggest that chronic deletion of Got1 did not result in decreased Treg cell differentiation or enhanced TH17 cell differentiation and EAE disease scores, but instead caused around a twofold reduction in EAE disease scores at the early disease-onset stage (from W. Xu et al.2, data not shown). In another immunization model using gp66, mice with a chronic deletion of Got1 showed a slightly increased percentage of FOXP3+ cells as well as IL-17+ cells (extended data figure 3 of ref. 2). Mechanistically, W. Xu et al.2 showed that chronic deletion of Got1 led to increased mRNA expression of genes related to glycolysis, oxidative phosphorylation (OXPHOS) and fatty-acid metabolism pathways, as well as increased metabolic activity of most major metabolic pathways (extended data figure 2b–d,j of ref. 2). Given the key roles of cellular metabolism in signalling, transcription and epigenetics, it might be conceivable that cells could adapt to the absence of GOT1 during development through various compensatory mechanisms3,4. Nonetheless, those discrepancies would need to be studied further.

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Fig. 1: Acute deletion of Got1 inhibits TH17 cells, promotes Treg cell differentiation and ameliorates mouse EAE disease, whereas chronic deletion of Got1 upregulates Gpt2.

Data availability

The data generated in this study are available from the corresponding authors on request.

References

  1. Xu, T. et al. Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism. Nature 548, 228–233 (2017).

    Article  CAS  ADS  Google Scholar 

  2. Xu, W. et al. GOT1 constrains TH17 cell differentiation, while promoting iTreg cell differentiation. Nature, https://doi.org/10.1038/s41586-022-05602-3 (2023).

  3. Brolosy, et al. Genetic compensation triggered by mutant mRNA degradation. Nature 568, 193–196 (2019).

    Article  ADS  Google Scholar 

  4. Ma, et al. PTC-bearing mRNA elicits a genetic compensation response via Upf3a and COMPASS components. Nature 568, 259–263 (2019).

    Article  CAS  ADS  Google Scholar 

  5. Wise, D. R. et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc. Natl Acad. Sci. USA 105, 18782–18787 (2008).

    Article  CAS  ADS  Google Scholar 

  6. Toney, M. D. Aspartate aminotransferase: an old dog teaches new tricks. Arch. Biochem. Biophys. 544, 119–127 (2014).

    Article  CAS  Google Scholar 

  7. Alberty, R. A. Biochemical Thermodynamics: Applications of Mathematica (John Wiley & Sons, 2006).

  8. Birsoy, et al. An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Cell 162, 540–551 (2015).

    Article  CAS  Google Scholar 

  9. Son, J. et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496, 101–105 (2013).

    Article  CAS  ADS  Google Scholar 

  10. Allen, E. L. et al. Differential aspartate usage identifies a subset of cancer cells particularly dependent on OGDH. Cell Rep. 17, 876–890 (2016).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank T. Buch for his help by providing Cd4-creERT2 mice; the staff members of the Animal Facility at Sun Yat-sen University for providing the support in mouse housing and care; and the staff members of the FACS facility of Zhongshan School of Medicine, Sun Yat-sen University for technical support. The newly generated data are part of the projects 81971530 (to T.X.) supported by the National Natural Science Foundation of China and 2018YFA0800300 from National Key R&D Program of China, China (T.X.).

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Author notes

  1. These authors jointly supervised this work: Tao Xu, Chen Dong, Edward M. Driggers, Sheng Ding

Authors and Affiliations

  1. Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China

    Tao Xu & Zhen Qin

  2. Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China

    Xiaohu Wang & Chen Dong

  3. Agios Pharmaceuticals, Cambridge, MA, USA

    Edward M. Driggers

  4. School of Pharmaceutical Sciences, Tsinghua University, Beijing, China

    Sheng Ding

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  1. Tao Xu
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Contributions

T.X. and Z.Q. performed the experiments. T.X., Z.Q., X.W., E.M.D. and S.D. wrote the manuscript. C.D., E.M.D. and S.D. edited the manuscript. All of the authors read and approved the manuscript. Because this is a Reply to the Comment by W. Xu et al.2, we only included those authors who were responsible for the previous study1, who were involved in addressing the comments by W. Xu et al.2 and who produced data included in the Reply. The other authors from our previous study1 are therefore not included.

Corresponding authors

Correspondence to Tao Xu, Chen Dong, Edward M. Driggers or Sheng Ding.

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Xu, T., Qin, Z., Wang, X. et al. Reply to: GOT1 constrains TH17 cell differentiation, while promoting iTreg cell differentiation. Nature 614, E12–E14 (2023). https://doi.org/10.1038/s41586-022-05603-2

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