Cells respond to starvation by shutting down protein synthesis and by activating catabolic processes, including autophagy, to recycle nutrients. This two-pronged response is mediated by the integrated stress response (ISR) through phosphorylation of eIF2α, which represses protein translation, and by inhibition of mTORC1 signaling, which promotes autophagy also through a stress-responsive transcriptional program. Implementation of such a program, however, requires protein synthesis, thus conflicting with general repression of translation. How is this mismatch resolved? We found that the main regulator of the starvation-induced transcriptional program, TFEB, counteracts protein synthesis inhibition by directly activating expression of GADD34, a component of the protein phosphatase 1 complex that dephosphorylates eIF2α. We discovered that GADD34 plays an essential role in autophagy by tuning translation during starvation, thus enabling lysosomal biogenesis and a sustained autophagic flux. Hence, the TFEB-GADD34 axis integrates the mTORC1 and ISR pathways in response to starvation.

细胞通过关闭蛋白质合成和激活分解代谢过程（包括自噬）来循环营养物质来应对饥饿。这种双管齐下的反应是由综合应激反应 (ISR) 通过抑制蛋白质翻译的 eIF2α 磷酸化和抑制 mTORC1 信号传导介导的，这也通过应激反应性转录程序促进自噬。然而，这种程序的实施需要蛋白质合成，因此与一般的翻译抑制相冲突。这种不匹配是如何解决的？我们发现饥饿诱导的转录程序的主要调节因子 TFEB 通过直接激活 GADD34 的表达来抵消蛋白质合成抑制，GADD34 是使 eIF2α 去磷酸化的蛋白磷酸酶 1 复合物的一种成分。我们发现 GADD34 通过在饥饿期间调整翻译在自噬中发挥重要作用，从而使溶酶体生物发生和持续的自噬通量成为可能。因此，TFEB-GADD34 轴整合了 mTORC1 和 ISR 通路以响应饥饿。