Maurin Anne-Catherine, Parry Laurent, B'chir Wafa, Carraro Valérie, Coudy-Gandilhon Cécile, Chaouki Ghita, Chaveroux Cédric, Mordier Sylvie, Martinie Brigitte, Reinhardt Vanessa, Jousse Céline, Bruhat Alain, Codogno Patrice, Averous Julien, Fafournoux Pierre
Unité de Nutrition Humaine, INRAE, Université Clermont Auvergne, UMR 1019, F-63000 Clermont-Ferrand, France.
Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS 5286, Centre Léon Bérard, Université Lyon, F-69373, Lyon, France.
Autophagy Rep. 2022 Apr 7;1(1):119-142. doi: 10.1080/27694127.2022.2049045. eCollection 2022.
The ability to adapt the proteolysis rates based on fluctuations in essential amino acid (EAA) availability is essential for life. The GCN2-eIF2α-ATF4 signaling pathway is involved in the adaptive response to EAA deprivations. Our previous results demonstrated that activation of this pathway is involved in upregulating the expression of many autophagy genes at the transcriptional level thanks to the transcription factor ATF4. In the present study, we investigated whether the kinase GCN2 is also involved in early upregulation of the autophagic process in response to EAA deficiencies, thereby contributing to a rapid increase in the proteolysis rate. We observed that a one-hour leucine deprivation upregulated autophagy in both cultured cells and in mouse liver, as reflected by an increase in both [S278]-ATG16L1 phosphorylation and LC3B conversion, and decreased p62 protein level. Using cells and mice with genetic ablation of as well as genetic reconstitution experiments , data showed that GCN2 was required for this upregulation of autophagy. Downstream GCN2, the phosphorylation of eIF2α was necessary, while ATF4 was not. Overall, these findings revealed a major role of GCN2-eIF2α signaling in the regulation of autophagy in response to short-term EAA deprivation.
根据必需氨基酸（EAA）可用性的波动来调整蛋白水解速率的能力对生命至关重要。GCN2-eIF2α-ATF4信号通路参与了对EAA剥夺的适应性反应。我们之前的结果表明，由于转录因子ATF4，该通路的激活在转录水平上参与上调许多自噬基因的表达。在本研究中，我们调查了激酶GCN2是否也参与了对EAA缺乏的自噬过程的早期上调，从而导致蛋白水解速率的快速增加。我们观察到，一小时的亮氨酸剥夺上调了培养细胞和小鼠肝脏中的自噬，这通过[S278]-ATG16L1磷酸化和LC3B转化的增加以及p62蛋白水平的降低得以体现。使用基因敲除的细胞和小鼠以及基因重组实验，数据表明GCN2是这种自噬上调所必需的。在GCN2的下游，eIF2α的磷酸化是必需的，而ATF4则不是。总体而言，这些发现揭示了GCN2-eIF2α信号在响应短期EAA剥夺时对自噬调节中的主要作用。
