2-Hydroxypropyl-β-cyclodextrin Promotes Transcription Factor EB- mediated Activation of Autophagy

Background: The drug delivery vehicle 2-hydroxypropyl--cyclodextrin (HPCD) prevents cholesterol storage. Results: HPCD treatment induces TFEB mediated activation of autophagy and clearance of the autophagic substrate ceroid lipopigment. Conclusion: HPCD administration results in enhancement of the innate autophagic clearance capacity. Significance: Dissecting the cellular pathways impacted by HPCD is crucial to design HPCD-based therapeutic modalities. 2-Hydroxypropyl--cyclodextrin (HPCD) 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 HPCD are still poorly defined. Here, we show that cell treatment with HPCD 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. HPCD 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, HPCD-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 HPCD treatment, which will inform the development of safe HPCD-based therapeutic modalities and may enable engineering HPCD as a platform technology to reduce the accumulation of lysosomal storage material.