Lysosome biogenesis in health and disease.
Lysosome biogenesis in health and disease.
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DOI：
10.1111/jnc.14564
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发表时间：
2019-03
影响因子：
4.7
通讯作者：
Sardiello M
中科院分区：
文献类型：
--
作者：
Bajaj L;Lotfi P;Pal R;Ronza AD;Sharma J;Sardiello M
本文综述了调节溶酶体生物合成的途径，这些途径与许多退行性贮积病有关，包括溶酶体贮积病和迟发性神经退行性疾病。溶酶体蛋白在内质网中合成，并通过分泌途径运输到内溶酶体系统。已经表征了几种受体，其执行溶酶体蛋白质的高尔基体后运输。它们中的一些基于特定的氨基酸特征识别它们的货物蛋白，另一些基于仅在溶酶体蛋白上发现的特定聚糖修饰。几乎所有用于溶酶体生物发生的受体都在转录因子EB（TFEB）的转录控制下，TFEB是溶酶体系统的主调节因子。TFEB协调溶酶体水解酶、溶酶体膜蛋白和自噬蛋白的表达，以响应感测溶酶体应激的途径和细胞的营养条件以及其他刺激。TFEB在溶酶体贮积症中被激活，但令人惊讶的是，由于限制TFEB表达或激活的特定有害相互作用，其功能在一些迟发性神经退行性贮积病如阿尔茨海默病和帕金森病中受损。因此，破坏的TFEB功能可能在这些疾病的发病机制中起作用。在退行性胆积病的动物模型中的多项研究表明，TFEB的外源性表达和内源性TFEB的药理学激活减弱了疾病表型。这些结果突出了TFEB介导的溶酶体生物发生的增强和作为抵抗这些疾病进展的候选策略的功能。本文综述了转录因子EB（TFEB）是如何参与溶酶体生物合成和退行性胆积病。TFEB协调参与自噬-溶酶体途径的蛋白质的表达，包括溶酶体酶及其转运蛋白。TFEB由于溶酶体应激而在溶酶体贮积症中被激活，但由于限制TFEB表达或激活的特定有害相互作用，TFEB功能在一些迟发性神经退行性贮积病中受损。TFEB的表达或活化增加导致自噬-溶酶体途径的增强，并改善溶酶体胆积症和其他退行性胆积症模型中的疾病表型。
This review focuses on the pathways that regulate lysosome biogenesis and that are implicated in numerous degenerative storage diseases, including lysosomal storage disorders and late-onset neurodegenerative diseases. Lysosomal proteins are synthesized in the endoplasmic reticulum and trafficked to the endolysosomal system through the secretory route. Several receptors have been characterized that execute post-Golgi trafficking of lysosomal proteins. Some of them recognize their cargo proteins based on specific amino acid signatures, others based on a particular glycan modification that is exclusively found on lysosomal proteins. Nearly all receptors serving lysosome biogenesis are under the transcriptional control of transcription factor EB (TFEB), a master regulator of the lysosomal system. TFEB coordinates the expression of lysosomal hydrolases, lysosomal membrane proteins, and autophagy proteins in response to pathways sensing lysosomal stress and the nutritional conditions of the cell among other stimuli. TFEB is primed for activation in lysosomal storage disorders but surprisingly its function is impaired in some late-onset neurodegenerative storage diseases like Alzheimer’s and Parkinson’s, due to specific detrimental interactions that limit TFEB expression or activation. Thus, disrupted TFEB function presumably plays a role in the pathogenesis of these diseases. Multiple studies in animal models of degenerative storage diseases have shown that exogenous expression of TFEB and pharmacological activation of endogenous TFEB attenuate disease phenotypes. These results highlight TFEB-mediated enhancement of lysosomal biogenesis and function as a candidate strategy to counteract the progression of these diseases. This review discusses how the transcription factor EB (TFEB) is implicated in lysosomal biogenesis and degenerative storage diseases. TFEB coordinates the expression of proteins participating in the autophagy-lysosome pathway, including lysosomal enzymes and their transporters. TFEB is primed for activation in lysosomal storage disorders due to lysosomal stress, but TFEB function is impaired in some late-onset neurodegenerative storage diseases due to specific detrimental interactions that limit TFEB expression or activation. Increased expression or activation of TFEB results in the enhancement of the autophagy-lysosome pathway and ameliorates disease phenotypes in models of lysosomal storage disorders and other degenerative storage diseases.