Shandong Key Laboratory of Infection and Immunity, Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, Shandong, China.
Shandong Key Laboratory of Infection and Immunity, Department of Pathogenic Biology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, Shandong, China.
Cell Death Differ. 2021 Apr;28(4):1237-1250. doi: 10.1038/s41418-020-00646-2. Epub 2020 Oct 25.
Transcription factor EB (TFEB) is a master regulator of autophagy and lysosomal biogenesis. The post-translational phosphorylation modulations of TFEB by mTOR and ERK signaling can determine its nucleocytoplasmic shuttling and activity in response to nutrient availability. However, regulations of TFEB at translational level are rarely known. Here, we found that programmed cell death 4 (PDCD4), a tumor suppressor, decreased levels of nuclear TFEB to inhibit lysosome biogenesis and function. Mechanistically, PDCD4 reduces global pool of TFEB by suppressing TFEB translation in an eIF4A-dependent manner, rather than influencing mTOR- and ERK2-dependnet TFEB nucleocytoplasmic shuttling. Both of MA3 domains within PDCD4 are required for TFEB translation inhibition. Furthermore, TFEB is required for PDCD4-mediated lysosomal function suppression. In the tumor microenvironment, PDCD4 deficiency promotes the anti-tumor effect of macrophage via enhancing TFEB expression. Our research reveals a novel PDCD4-dependent TFEB translational regulation and supports PDCD4 as a potential therapeutic target for lysosome dysfunction related diseases.
转录因子 EB（TFEB）是自噬和溶酶体生物发生的主要调节因子。mTOR 和 ERK 信号对 TFEB 的翻译后磷酸化调节可以决定其核质穿梭和对营养可用性的反应活性。然而，TFEB 在翻译水平上的调节很少被知晓。在这里，我们发现程序性细胞死亡 4（PDCD4），一种肿瘤抑制因子，降低核 TFEB 的水平以抑制溶酶体生物发生和功能。在机制上，PDCD4 通过抑制 eIF4A 依赖性 TFEB 翻译而不是影响 mTOR 和 ERK2 依赖性 TFEB 核质穿梭来减少 TFEB 的整体池。PDCD4 内的两个 MA3 结构域都需要抑制 TFEB 翻译。此外，TFEB 是 PDCD4 介导的溶酶体功能抑制所必需的。在肿瘤微环境中，PDCD4 缺乏通过增强 TFEB 表达促进巨噬细胞的抗肿瘤作用。我们的研究揭示了一种新的 PDCD4 依赖的 TFEB 翻译调控，并支持 PDCD4 作为与溶酶体功能障碍相关疾病的潜在治疗靶点。
