Proteasome Inhibition Activates Autophagy-Lysosome Pathway Associated With TFEB Dephosphorylation and Nuclear Translocation
Proteasome Inhibition Activates Autophagy-Lysosome Pathway Associated With TFEB Dephosphorylation and Nuclear Translocation
复制标题
蛋白酶体抑制激活与 TFEB 去磷酸化和核转位相关的自噬-溶酶体途径
DOI：
10.3389/fcell.2019.00170
复制
发表时间：
2019-08-22
影响因子：
5.5
通讯作者：
Wu, Yili
中科院分区：
文献类型：
--
作者：
Li, Chunyan;Wang, Xin;Wu, Yili
泛素-蛋白酶体途径(UPS)和自噬-溶酶体途径(ALP)是蛋白质降解的两条主要途径，对蛋白质的稳定起关键作用。越来越多的证据表明，蛋白酶体抑制诱导的碱性磷酸酶激活是一种适应性反应。转录因子EB(TFEB)是碱性磷酸酶的主要调节因子。然而，TFEB的特性及其在蛋白酶体抑制诱导的碱性磷酸酶激活中的作用还没有得到充分的研究。在此，我们报道了TFEB在神经元样细胞中的半衰期约为13.5h，在神经元样细胞和非神经元细胞中TFEB均通过蛋白酶体途径降解。此外，蛋白酶体损伤不仅促进了TFEB的积聚，还促进了其去磷酸化和核转位。此外，蛋白酶体抑制诱导的TFEB积聚、去磷酸化和核转位显著增加了一些参与ALP激活的TFEB下游基因的表达，包括微管相关蛋白1B轻链3(LC3)，尤其是LC3-II、组织蛋白酶D和溶酶体相关膜蛋白1(LAMP1)。此外，我们还证明，蛋白酶体抑制增加了自噬小体的生物发生，但不会削弱自噬通量。我们的研究促进了对TFEB功能的理解，并表明TFEB可能是蛋白酶体损伤诱导的ALP激活的关键介质。
Ubiquitin-proteasome pathway (UPS) and autophagy-lysosome pathway (ALP) are the two major protein degradation pathways, which are critical for proteostasis. Growing evidence indicates that proteasome inhibition-induced ALP activation is an adaptive response. Transcription Factor EB (TFEB) is a master regulator of ALP. However, the characteristics of TFEB and its role in proteasome inhibition-induced ALP activation are not fully investigated. Here we reported that the half-life of TFEB is around 13.5 h in neuronal-like cells, and TFEB is degraded through proteasome pathway in both neuronal-like and non-neuronal cells. Moreover, proteasome impairment not only promotes TFEB accumulation but also facilitates its dephosphorylation and nuclear translocation. In addition, proteasome inhibition-induced TFEB accumulation, dephosphorylation and nuclear translocation significantly increases the expression of a number of TFEB downstream genes involved in ALP activation, including microtubule-associated protein 1B light chain-3 (LC3), particularly LC3-II, cathepsin D and lysosomal-associated membrane protein 1 (LAMP1). Furthermore, we demonstrated that proteasome inhibition increases autophagosome biogenesis but not impairs autophagic flux. Our study advances the understanding of features of TFEB and indicates that TFEB might be a key mediator of proteasome impairment-induced ALP activation.