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000284615 245__ $$aThe malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate.
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000284615 520__ $$aThe 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.
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000284615 7001_ $$aMa, Sicong$$b1
000284615 7001_ $$0P:(DE-HGF)0$$aMing, Yanan$$b2
000284615 7001_ $$0P:(DE-He78)f05eabc961bc296c088b3510d6429d02$$aMadi, Alaa Abdelghani Mohamed$$b3$$udkfz
000284615 7001_ $$0P:(DE-He78)32b6d84a1ad5f50401b97559993ad65d$$aMieg, Alessa$$b4$$udkfz
000284615 7001_ $$0P:(DE-He78)b099c4255c1bff642f4d338ef157596e$$aHering, Marvin$$b5$$udkfz
000284615 7001_ $$0P:(DE-He78)a97252706aa90b10eb9e489f0018ba96$$aZettl, Ferdinand$$b6$$udkfz
000284615 7001_ $$0P:(DE-He78)6c644df06759d9295db52a00eac44c0f$$aMohr, Kerstin$$b7$$udkfz
000284615 7001_ $$0P:(DE-He78)ad4b5f19b891aeb51245ce42ff3d92ff$$aten Bosch, Nora$$b8$$udkfz
000284615 7001_ $$0P:(DE-He78)de81d854a499aca413da2a07204b2dfe$$aStichling, Diana$$b9$$udkfz
000284615 7001_ $$aBuettner, Michael$$b10
000284615 7001_ $$aPoschet, Gernot$$b11
000284615 7001_ $$aKlinke, Glynis$$b12
000284615 7001_ $$aSchulz, Michael$$b13
000284615 7001_ $$aKunze-Rohrbach, Nina$$b14
000284615 7001_ $$aKerber, Carolin$$b15
000284615 7001_ $$aKlein, Isabel Madeleine$$b16
000284615 7001_ $$aWu, Jingxia$$b17
000284615 7001_ $$aWang, Xi$$b18
000284615 7001_ $$0P:(DE-He78)0b7ce76033a6756b91f5bfb12602e20b$$aCui, Guoliang$$b19$$eLast author$$udkfz
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