Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510.
Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510.
Proc Natl Acad Sci U S A. 2023 Aug;120(31):e2303789120. doi: 10.1073/pnas.2303789120. Epub 2023 Jul 24.
Cells maintain optimal levels of lysosome degradative activity to protect against pathogens, clear waste, and generate nutrients. Here, we show that LRRK2, a protein that is tightly linked to Parkinson's disease, negatively regulates lysosome degradative activity in macrophages and microglia via a transcriptional mechanism. Depletion of LRRK2 and inhibition of LRRK2 kinase activity enhanced lysosomal proteolytic activity and increased the expression of multiple lysosomal hydrolases. Conversely, the kinase hyperactive LRRK2 G2019S Parkinson's disease mutant suppressed lysosomal degradative activity and gene expression. We identified MiT-TFE transcription factors (TFE3, TFEB, and MITF) as mediators of LRRK2-dependent control of lysosomal gene expression. LRRK2 negatively regulated the abundance and nuclear localization of these transcription factors and their depletion prevented LRRK2-dependent changes in lysosome protein levels. These observations define a role for LRRK2 in controlling lysosome degradative activity and support a model wherein LRRK2 hyperactivity may increase Parkinson's disease risk by suppressing lysosome degradative activity.
细胞维持最佳的溶酶体降解活性水平，以抵御病原体、清除废物和产生营养物质。在这里，我们表明，LRRK2 是一种与帕金森病密切相关的蛋白质，通过转录机制负调控巨噬细胞和小胶质细胞中的溶酶体降解活性。LRRK2 的耗竭和 LRRK2 激酶活性的抑制增强了溶酶体蛋白水解活性，并增加了多个溶酶体水解酶的表达。相反，激酶活性升高的 LRRK2 G2019S 帕金森病突变体抑制了溶酶体降解活性和基因表达。我们确定了 MiT-TFE 转录因子（TFE3、TFEB 和 MITF）作为 LRRK2 依赖性溶酶体基因表达调控的介质。LRRK2 负调控这些转录因子的丰度和核定位，其耗竭可防止 LRRK2 依赖性溶酶体蛋白水平变化。这些观察结果定义了 LRRK2 在控制溶酶体降解活性中的作用，并支持 LRRK2 过度活跃可能通过抑制溶酶体降解活性增加帕金森病风险的模型。
