TFEB regulates lysosomal proteostasis
TFEB regulates lysosomal proteostasis
复制标题
DOI：
10.1093/hmg/ddt052
复制
发表时间：
2013-05-15
影响因子：
3.5
通讯作者：
Segatori, Laura
中科院分区：
文献类型：
--
作者：
Song, Wensi;Wang, Fan;Segatori, Laura
功能丧失疾病通常是由导致蛋白质错误折叠和降解的不稳定突变引起的。调节先天蛋白质稳态（蛋白质稳态）能力可能会导致突变变体的天然折叠的挽救，从而改善疾病表型。在溶酶体贮积症 (LSD) 中，许多高度流行的等位基因具有错义突变，这些突变不会损害酶的催化活性，但会破坏其天然结构的稳定性，导致错误折叠蛋白质的降解。增强细胞折叠能力能够挽救这些不稳定突变酶的天然生物功能结构。然而，目前尚不清楚溶酶体系统特异的蛋白质稳态调节剂。在这里，我们研究了转录因子 EB (TFEB)（溶酶体生物合成和功能的主要调节因子）在调节 LSD 溶酶体蛋白质稳态中的作用。我们发现，TFEB 激活会导致严重不稳定的葡萄糖脑苷脂酶 (GC) 变体的折叠、运输和溶酶体活性增强，该变体与最常见的 LSD 戈谢病 (GD) 的发展相关。 TFEB 特异性诱导 GC 以及参与折叠和溶酶体运输的关键基因的表达，从而增强突变酶库及其通过分泌途径的加工。 TFEB 激活还可以挽救与另一种 LSD（TaySachs 病）的发展相关的 β-己糖胺酶突变体的活性，因此表明 TFEB 介导的蛋白质稳态调节对于挽救 LSD 中的不稳定突变具有普遍适用性。总之，我们的研究结果将 TFEB 确定为溶酶体蛋白质稳态的特异性调节剂，并表明 TFEB 可用作挽救 LSD 中酶稳态的治疗靶点。
Loss-of-function diseases are often caused by destabilizing mutations that lead to protein misfolding and degradation. Modulating the innate protein homeostasis (proteostasis) capacity may lead to rescue of native folding of the mutated variants, thereby ameliorating the disease phenotype. In lysosomal storage disorders (LSDs), a number of highly prevalent alleles have missense mutations that do not impair the enzymes catalytic activity but destabilize its native structure, resulting in the degradation of the misfolded protein. Enhancing the cellular folding capacity enables rescuing the native, biologically functional structure of these unstable mutated enzymes. However, proteostasis modulators specific for the lysosomal system are currently unknown. Here, we investigate the role of the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and function, in modulating lysosomal proteostasis in LSDs. We show that TFEB activation results in enhanced folding, trafficking and lysosomal activity of a severely destabilized glucocerebrosidase (GC) variant associated with the development of Gaucher disease (GD), the most common LSD. TFEB specifically induces the expression of GC and of key genes involved in folding and lysosomal trafficking, thereby enhancing both the pool of mutated enzyme and its processing through the secretory pathway. TFEB activation also rescues the activity of a -hexosaminidase mutant associated with the development of another LSD, TaySachs disease, thus suggesting general applicability of TFEB-mediated proteostasis modulation to rescue destabilizing mutations in LSDs. In summary, our findings identify TFEB as a specific regulator of lysosomal proteostasis and suggest that TFEB may be used as a therapeutic target to rescue enzyme homeostasis in LSDs.