Dong Hoon Han1,*, Hee-Kyung Na2,*, Won Hoon Choi1, Jung Hoon Lee1, Yun Kyung Kim3, Cheolhee Won2, Seung-Han Lee1, Kwang Pyo Kim1, Jeff Kuret4, Dal-Hee Min2 & Min Jae Lee1
1 Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea. 2 Center for RNA Research, Department of Chemistry, Institute for Basic Science, Seoul National University, Seoul 151-747, Republic of Korea. 3 Center for Neuro-Medicine, Korea Institute of Science & Technology (KIST), Seoul 136-791, Republic of Korea. 4 Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio 43210, USA.
* These authors contributed equally to this work.
Correspondence to: Dal-Hee Min or Min Jae Lee
The 26S proteasome is the primary machinery that degrades ubiquitin (Ub)-conjugated proteins, including many proteotoxic proteins implicated in neurodegeneraton. It has been suggested that the elevation of proteasomal activity is tolerable to cells and may be beneficial to prevent the accumulation of protein aggregates. Here we show that purified proteasomes can be directly transported into cells through mesoporous silica nanoparticle-mediated endocytosis. Proteasomes that are loaded onto nanoparticles through non-covalent interactions between polyhistidine tags and nickel ions fully retain their proteolytic activity. Cells treated with exogenous proteasomes are more efficient in degrading overexpressed human tau than endogenous proteasomal substrates, resulting in decreased levels of tau aggregates. Moreover, exogenous proteasome delivery significantly promotes cell survival against proteotoxic stress caused by tau and reactive oxygen species. These data demonstrate that increasing cellular proteasome activity through the direct delivery of purified proteasomes may be an effective strategy for reducing cellular levels of proteotoxic proteins.