Progress in nanotechnology has led to a dramatic increase in the number of consumer products containing engineered nanoparticles (NPs). Because of their unique physicochemical properties, such as size and charge, engineered NPs are able to uniquely interact with biological systems; however, surprisingly little is known about the impact these interactions have on cell physiology.When NPs are internalized by cells, they are typically perceived as foreign or toxic material. As a result, NPs may activate autophagy, the main clearance pathway mediating degradation of cellular waste. Autophagy involves compartmentalization of substrates into autophagosomes, and fusion of autophagosomes with lysosomes to generate autophagolysosomes, where degradation occurs. Impairment of this fundamental catabolic pathway often results in accumulation of cellular waste or toxic substrates.It was recently shown that autophagosome and lysosome biogenesis is co-regulated by an overarching gene network (CLEAR network, Coordinated Lysosomal Expression and Regulation) and its master regulator, the transcription factor EB (TFEB). We have developed a series of in vitro model systems that allow us to investigate different steps of the autophagic pathway, including TFEB activation, fusion of autophagosomes with lysosomes, and clearance of autophagic material. Our preliminary results with gold and ceria NPs demonstrate that while most NPs induce TFEB activation and autophagosome formation, the specific physicochemical properties of NPs determine whether NP autophagy activators enhance autophagic clearance, or cause impairment of downstream autophagic processes. Using a series of analytical tools that allow us to monitor the autophagic flux from initiation to completion, we are exploring the relationship between the physicochemical properties of NPs and their interactions with the autophagy pathway, thereby linking macroscopic phenomena (e.g., toxicity) to molecular mechanisms. Results from this study will lead to the design of NPs with desired effect on autophagy, and ultimately, to the engineering of safe NP-containing products.

Understanding design rules for engineering nanoparticles with autophagy-inducing properties

247th National Meeting (2014)

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