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Programmed cell death 4 modulates lysosomal function by inhibiting TFEB translation
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2020-10-25 , DOI: 10.1038/s41418-020-00646-2
Xiaotong Chen 1 , Yetong Guan 1 , Yi Zhang 1 , Yufeng Jia 1 , Wen Li 1 , Chun Guo 1 , Yuan Li 1 , Xiaoyan Wang 1 , Yongyu Shi 1 , Qun Wang 1 , Faliang Zhu 1 , Yan Li 2 , Lining Zhang 1
Affiliation  

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.



中文翻译:

程序性细胞死亡 4 通过抑制 TFEB 翻译调节溶酶体功能

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 信号传导对 TFEB 的翻译后磷酸化调节可以确定其核质穿梭和响应营养可用性的活性。然而,翻译层面的 TFEB 法规鲜为人知。在这里,我们发现程序性细胞死亡 4 (PDCD4),一种肿瘤抑制因子,降低了核 TFEB 的水平,从而抑制了溶酶体的生物发生和功能。从机制上讲,PDCD4 通过以 eIF4A 依赖的方式抑制 TFEB 翻译,而不是影响 mTOR 和 ERK2 依赖的 TFEB 核质穿梭,从而减少了 TFEB 的全局池。PDCD4 中的两个 MA3 结构域都是 TFEB 翻译抑制所必需的。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表达来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 依赖性 TFEB 翻译调节,并支持 PDCD4 作为溶酶体功能障碍相关疾病的潜在治疗靶点。

更新日期:2020-10-28
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