The nutrient-responsive transcription factor TFE3 promotes autophagy, lysosomal biogenesis, and clearance of cellular debris.
The nutrient-responsive transcription factor TFE3 promotes autophagy, lysosomal biogenesis, and clearance of cellular debris.
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DOI：
10.1126/scisignal.2004754
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发表时间：
2014-01-21
影响因子：
7.3
通讯作者：
Puertollano R
中科院分区：
文献类型：
--
作者：
Martina JA;Diab HI;Lishu L;Jeong-A L;Patange S;Raben N;Puertollano R
调节溶酶体生物发生及其转录调节因子TFEB的基因网络的发现揭示了细胞监测溶酶体功能并对降解要求和环境线索作出反应。在这里，我们报告了转录因子E3（TFE 3）作为另一种溶酶体稳态调节因子的鉴定，该调节因子诱导ARPE-19细胞中参与饥饿和溶酶体应激的自噬和溶酶体生物合成的编码蛋白质的基因表达。我们发现，在营养充足的细胞中，TFE 3通过与活性Rag GTP酶相互作用被募集到溶酶体中，并表现出mTORC 1依赖性磷酸化。磷酸化的TFE 3通过其与胞质伴侣14-3-3的相互作用保留在胞质溶胶中。饥饿后，TFE 3迅速易位到细胞核，并结合到许多溶酶体基因启动子区的CLEAR元件，从而诱导溶酶体生物合成。内源性TFE 3的耗尽完全消除了ARPE-19细胞对饥饿的反应，表明TFE 3在营养感测和能量代谢调节中起着关键作用。此外，TFE 3的过表达引发溶酶体胞吐作用，并在溶酶体贮积症庞贝氏症的细胞模型中导致有效的细胞清除，从而将TFE 3鉴定为用于治疗溶酶体病症的潜在治疗靶标。
The discovery of a gene network regulating lysosomal biogenesis and its transcriptional regulator TFEB revealed that cells monitor lysosomal function and respond to degradation requirements and environmental cues. Here, we report the identification of transcription factor E3 (TFE3) as another regulator of lysosomal homeostasis that induced expression of genes encoding proteins involved in autophagy and lysosomal biogenesis in ARPE-19 cells in response to starvation and lysosomal stress. We found that in nutrient-replete cells, TFE3 was recruited to lysosomes through interaction with active Rag GTPases and exhibited mTORC1-dependent phosphorylation. Phosphorylated TFE3 was retained in the cytosol through its interaction with the cytosolic chaperone 14-3-3. Following starvation, TFE3 rapidly translocated to the nucleus and bound to the CLEAR elements present in the promoter region of many lysosomal genes, thereby inducing lysosomal biogenesis. Depletion of endogenous TFE3 entirely abolished the response of ARPE-19 cells to starvation, suggesting that TFE3 plays a critical role in nutrient sensing and regulation of energy metabolism. Furthermore, overexpression of TFE3 triggered lysosomal exocytosis and resulted in efficient cellular clearance in a cellular model of a lysosomal storage disorder, Pompe disease, thus identifying TFE3 as a potential therapeutic target for the treatment of lysosomal disorders.