Abstract
BackgroundA number of engineered nanoparticles induce autophagy, the main catabolic pathway that regulates bulk degradation of cytoplasmic material by the lysosomes. Depending on the specific physico-chemical properties of the nanomaterial, however, nanoparticle-induced autophagy may have different effects on cell physiology, ranging from enhanced autophagic degradation to blockage of autophagic flux. To investigate the molecular mechanisms underlying the impact of nanoparticle charge on the nature of the autophagic response, we tested polystyrene nanoparticles (50 nm) with neutral, anionic, and cationic surface charges.ResultsWe found all polystyrene nanoparticles investigated in this study to activate autophagy. We showed that internalization of polystyrene nanoparticles results in activation of the transcription factor EB, a master regulator of autophagy and lysosome biogenesis. Autophagic clearance, however, was observed to depend specifically on the charge of the nanoparticles. Particularly, we found that the autophagic response to polystyrene nanoparticles presenting a neutral or anionic surface involves enhanced clearance of autophagic cargo. Cell exposure to polystyrene nanoparticles presenting a cationic surface, on the other hand, results in transcriptional upregulation of the pathway, but also causes lysosomal dysfunction, ultimately resulting in blockage of autophagic flux.ConclusionsThis study furthers our understanding of the molecular mechanisms that regulate the autophagic response to nanoparticles, thus contributing essential design criteria for engineering benign nanomaterials.Electronic supplementary materialThe online version of this article (doi:10.1186/s12951-015-0149-6) contains supplementary material, which is available to authorized users.
Highlights
A number of engineered nanoparticles induce autophagy, the main catabolic pathway that regulates bulk degradation of cytoplasmic material by the lysosomes
Polystyrene nanoparticles activate Transcription factor EB (TFEB) in HeLa/TFEB cells To investigate the molecular mechanisms involved in the autophagic response to nanoparticles of different surface charge, we first analyzed the transcriptional regulatory network that controls autophagy activation by monitoring TFEB intracellular localization in cells treated with presenting neutral surfaces (PS), Carboxyl-functionalized polystyrene nanoparticles (PS-COOH), and Amine-functionalized polystyrene nanoparticles (PS-NH2)
HeLa/TFEB cells were treated with nanoparticles at final medium concentrations ranging from 10 to 100 μg/mL and TFEB intracellular localization was evaluated by confocal microscopy using Hoechst nuclear stain and an anti-FLAG antibody (Fig. 1a, b)
Summary
A number of engineered nanoparticles induce autophagy, the main catabolic pathway that regulates bulk degradation of cytoplasmic material by the lysosomes. Engineered nanoparticles are widely explored for a variety of biomedical applications, including drug delivery [1,2,3], in vitro and in vivo diagnostics [4, 5], and production of biocompatible materials [6, 7]. Because of their unique physical and chemical properties, nanoparticles interact with biological components and systems, which operate at the nanoscale. The molecular mechanisms that govern the autophagic response to nanoparticle internalization remain unclear
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