The eIF2 kinase GCN2 directs keratinocyte collective cell migration during wound healing via coordination of reactive oxygen species and amino acids.
The eIF2 kinase GCN2 directs keratinocyte collective cell migration during wound healing via coordination of reactive oxygen species and amino acids.
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DOI：
10.1016/j.jbc.2021.101257
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Wek RC
中科院分区：
文献类型：
--
作者：
Miles RR;Amin PH;Diaz MB;Misra J;Aukerman E;Das A;Ghosh N;Guith T;Knierman MD;Roy S;Spandau DF;Wek RC
皮肤伤口的愈合需要上皮角质形成细胞的集体迁移以将伤口床与环境密封。然而，协调这种集体迁移的信号事件尚不清楚。在这份报告中，我们解决的作用，磷酸化的真核细胞起始因子2（eIF 2）和伴随的基因表达在伤口愈合。体外人角质形成细胞单层的损伤导致eIF 2激酶GCN 2的快速活化。我们确定GCN 2的缺失或药理学抑制显著延迟集体细胞迁移和伤口闭合。全球转录组学，生物化学和细胞分析表明，GCN 2是必要的维持细胞内的游离氨基酸，特别是半胱氨酸，以及协调RAC 1-GTP驱动的活性氧（ROS）的产生，片状伪足的形成，和局灶性粘附动力学角质形成细胞受伤。使用GCN 2缺陷小鼠的体内实验验证了eIF 2激酶在完整皮肤中伤口愈合期间的作用。这些结果表明，GCN 2对于适当诱导集体细胞迁移至关重要，并且在协调皮肤伤口的再上皮化中起关键作用。
Healing of cutaneous wounds requires the collective migration of epithelial keratinocytes to seal the wound bed from the environment. However, the signaling events that coordinate this collective migration are unclear. In this report, we address the role of phosphorylation of eukaryotic initiation factor 2 (eIF2) and attendant gene expression during wound healing. Wounding of human keratinocyte monolayers in vitro led to the rapid activation of the eIF2 kinase GCN2. We determined that deletion or pharmacological inhibition of GCN2 significantly delayed collective cell migration and wound closure. Global transcriptomic, biochemical, and cellular analyses indicated that GCN2 is necessary for maintenance of intracellular free amino acids, particularly cysteine, as well as coordination of RAC1-GTP-driven reactive oxygen species (ROS) generation, lamellipodia formation, and focal adhesion dynamics following keratinocyte wounding. In vivo experiments using mice deficient for GCN2 validated the role of the eIF2 kinase during wound healing in intact skin. These results indicate that GCN2 is critical for appropriate induction of collective cell migration and plays a critical role in coordinating the re-epithelialization of cutaneous wounds.
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影响因子：
14.9
作者：
Ait Ghezala H;Jolles B;Salhi S;Castrillo K;Carpentier W;Cagnard N;Bruhat A;Fafournoux P;Jean-Jean O
通讯作者：
Jean-Jean O
影响因子：
5.3
作者：
Lassot, I;Ségéral, E;Margottin-Goguet, F
通讯作者：
Margottin-Goguet, F
DOI：
10.1083/jcb.201612069
发表时间：
2018-02-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lawson CD;Ridley AJ
通讯作者：
Ridley AJ
DOI：
10.1007/978-1-62703-505-7_15
发表时间：
2013
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Chen JS;Longaker MT;Gurtner GC
通讯作者：
Gurtner GC
DOI：
10.4049/jimmunol.1502270
发表时间：
2016-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Das A;Ghatak S;Sinha M;Chaffee S;Ahmed NS;Parinandi NL;Wohleb ES;Sheridan JF;Sen CK;Roy S
通讯作者：
Roy S