From the Departments of Chemical and Biomolecular Engineering.
J Biol Chem. 2014 Apr 4;289(14):10211-22. doi: 10.1074/jbc.M113.506246. Epub 2014 Feb 20.
2-Hydroxypropyl-β-cyclodextrin (HPβCD) is a Food and Drug Administration-approved excipient used to improve the stability and bioavailability of drugs. Despite its wide use as a drug delivery vehicle and the recent approval of a clinical trial to evaluate its potential for the treatment of a cholesterol storage disorder, the cellular pathways involved in the adaptive response that is activated upon exposure to HPβCD are still poorly defined. Here, we show that cell treatment with HPβCD results in the activation of the transcription factor EB, a master regulator of lysosomal function and autophagy, and in enhancement of the cellular autophagic clearance capacity. HPβCD administration promotes transcription factor EB-mediated clearance of proteolipid aggregates that accumulate due to inefficient activity of the lysosome-autophagy system in cells derived from a patient with a lysosomal storage disorder. Interestingly, HPβCD-mediated activation of autophagy was found not to be associated with activation of apoptotic pathways. This study provides a mechanistic understanding of the cellular response to HPβCD treatment, which will inform the development of safe HPβCD-based therapeutic modalities and may enable engineering HPβCD as a platform technology to reduce the accumulation of lysosomal storage material.
2-羟丙基-β-环糊精（HPβCD）是一种获得美国食品和药物管理局批准的辅料，用于提高药物的稳定性和生物利用度。尽管它被广泛用作药物递送载体，并且最近批准了一项临床试验来评估其治疗胆固醇储存障碍的潜力，但在接触 HPβCD 时激活的适应性反应所涉及的细胞途径仍未得到很好的定义。在这里，我们表明，用 HPβCD 处理细胞会导致转录因子 EB 的激活，转录因子 EB 是溶酶体功能和自噬的主要调节剂，并增强细胞自噬清除能力。HPβCD 的给药促进了由于溶酶体-自噬系统在来自溶酶体储存障碍患者的细胞中活性不足而积累的蛋白脂筏聚集体的转录因子 EB 介导的清除。有趣的是，发现 HPβCD 介导的自噬激活与凋亡途径的激活无关。这项研究提供了对细胞对 HPβCD 治疗反应的机制理解，这将为安全的基于 HPβCD 的治疗模式的开发提供信息，并可能使 HPβCD 工程化作为一种平台技术来减少溶酶体储存物质的积累。
