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@ARTICLE{Weisshaar:284615,
author = {N. Weisshaar$^*$ and S. Ma and Y. Ming and A. A. M.
Madi$^*$ and A. Mieg$^*$ and M. Hering$^*$ and F. Zettl$^*$
and K. Mohr$^*$ and N. ten Bosch$^*$ and D. Stichling$^*$
and M. Buettner and G. Poschet and G. Klinke and M. Schulz
and N. Kunze-Rohrbach and C. Kerber and I. M. Klein and J.
Wu and X. Wang and G. Cui$^*$},
title = {{T}he malate shuttle detoxifies ammonia in exhausted {T}
cells by producing 2-ketoglutarate.},
journal = {Nature immunology},
volume = {24},
number = {11},
issn = {1529-2908},
address = {London},
publisher = {Springer Nature Limited},
reportid = {DKFZ-2023-02034},
pages = {1921-1932},
year = {2023},
note = {2023 Nov;24(11):1921-1932 / #EA:D192#LA:D192# / HI-TRON},
abstract = {The malate shuttle is traditionally understood to maintain
NAD+/NADH balance between the cytosol and mitochondria.
Whether the malate shuttle has additional functions is
unclear. Here we show that chronic viral infections induce
CD8+ T cell expression of GOT1, a central enzyme in the
malate shuttle. Got1 deficiency decreased the NAD+/NADH
ratio and limited antiviral CD8+ T cell responses to chronic
infection; however, increasing the NAD+/NADH ratio did not
restore T cell responses. Got1 deficiency reduced the
production of the ammonia scavenger 2-ketoglutarate (2-KG)
from glutaminolysis and led to a toxic accumulation of
ammonia in CD8+ T cells. Supplementation with 2-KG
assimilated and detoxified ammonia in Got1-deficient T cells
and restored antiviral responses. These data indicate that
the major function of the malate shuttle in CD8+ T cells is
not to maintain the NAD+/NADH balance but rather to detoxify
ammonia and enable sustainable ammonia-neutral glutamine
catabolism in CD8+ T cells during chronic infection.},
cin = {D192},
ddc = {610},
cid = {I:(DE-He78)D192-20160331},
pnm = {314 - Immunologie und Krebs (POF4-314)},
pid = {G:(DE-HGF)POF4-314},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:37813964},
doi = {10.1038/s41590-023-01636-5},
url = {https://inrepo02.dkfz.de/record/284615},
}