Stress Kinase GCN2 Controls the Proliferative Fitness and Trafficking of Cytotoxic T Cells Independent of Environmental Amino Acid Sensing.
Stress Kinase GCN2 Controls the Proliferative Fitness and Trafficking of Cytotoxic T Cells Independent of Environmental Amino Acid Sensing.
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DOI：
10.1016/j.celrep.2016.10.079
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发表时间：
2016-11-22
期刊：
影响因子：
8.8
通讯作者：
Murray PJ
中科院分区：
文献类型：
--
作者：
Van de Velde LA;Guo XJ;Barbaric L;Smith AM;Oguin TH 3rd;Thomas PG;Murray PJ
GCN2是通过磷酸化eIF2α阻断翻译的四种“应激激酶”之一。GCN2被认为结合不带电的trna来“感知”氨基酸的可用性。在哺乳动物中，表达吲哚胺双加氧酶的髓细胞局部消耗色氨酸，色氨酸在T细胞中被GCN2检测到，从而导致增殖停滞。据报道，gcn2缺陷T细胞在色氨酸受限时异位进入细胞周期。通过将GCN2缺陷菌株与TCR转基因背景杂交，我们发现GCN2对于诱导胁迫靶基因（如CHOP）至关重要。然而，gcn2缺陷的CD8+ T细胞在限制色氨酸、精氨酸、亮氨酸、赖氨酸或天冬酰胺时不能增殖，这与之前的研究结论相反。体外和体内增殖实验表明，gcn2缺陷的CD8+ T细胞具有CD4+ T细胞所没有的T细胞固有的增殖和运输缺陷。因此，GCN2是正常细胞毒性T细胞功能所必需的。
GCN2 is one of four ‘stress kinases’ that block translation by phosphorylating eIF2α. GCN2 is thought to bind uncharged tRNAs to ‘sense’amino acids availability. In mammals, myeloid cells expressing indoleamine dioxygenases locally deplete tryptophan, which is detected by GCN2 in T cells to cause proliferative arrest. GCN2-deficient T cells were reported to ectopically enter the cell cycle when tryptophan was limiting. Using GCN2-deficient strains crossed to TCR transgenic backgrounds, we found GCN2 is essential for induction of stress target genes such as CHOP. However, GCN2-deficient CD8+ T cells fail to proliferate in limiting tryptophan, arginine, leucine, lysine or asparagine, the opposite of what previous studies concluded. In vitro and in vivo proliferation experiments show that GCN2-deficient CD8+ T cells have T cell-intrinsic proliferative and trafficking defects not observed in CD4+ T cells. Thus GCN2 is required for normal cytotoxic T cell function.
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影响因子：
4.6
作者：
Averous J;Lambert-Langlais S;Mesclon F;Carraro V;Parry L;Jousse C;Bruhat A;Maurin AC;Pierre P;Proud CG;Fafournoux P
通讯作者：
Fafournoux P
DOI：
10.4049/jimmunol.1500993
发表时间：
2015-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Sharma N;Benechet AP;Lefrançois L;Khanna KM
通讯作者：
Khanna KM
影响因子：
16.8
作者：
Munn DH;Mellor AL
通讯作者：
Mellor AL
影响因子：
29
作者：
Maurin, AC;Jousse, C;Fafournoux, P
通讯作者：
Fafournoux, P
影响因子：
16
作者：
Harding, HP;Novoa, I;Ron, D
通讯作者：
Ron, D