title: Direct cellular delivery of human proteasomes to delay tau aggregation.
abstract: 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.
authors.affiliation: Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Han
authors.affiliation: Center for RNA Research, Department of Chemistry, Institute for Basic Science, Seoul National University, Seoul 151-747, Republic of Korea.
authors.forename: Hee-Kyung
authors.initials: HK
authors.lastname: Na
authors.affiliation: Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea.
authors.forename: Won Hoon
authors.initials: WH
authors.lastname: Choi
authors.affiliation: Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea.
authors.forename: Jung Hoon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science &Technology (KIST), Seoul 136-791, Republic of Korea.
authors.forename: Yun Kyung
authors.initials: YK
authors.lastname: Kim
authors.affiliation: Center for RNA Research, Department of Chemistry, Institute for Basic Science, Seoul National University, Seoul 151-747, Republic of Korea.
authors.forename: Cheolhee
authors.initials: C
authors.lastname: Won
authors.affiliation: Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea.
authors.forename: Seung-Han
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea.
authors.forename: Kwang Pyo
authors.initials: KP
authors.lastname: Kim
authors.affiliation: Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Kuret
authors.affiliation: Center for RNA Research, Department of Chemistry, Institute for Basic Science, Seoul National University, Seoul 151-747, Republic of Korea.
authors.forename: Dal-Hee
authors.initials: DH
authors.lastname: Min
authors.affiliation: Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea.
authors.forename: Min Jae
authors.initials: MJ
authors.lastname: Lee
mesh_terms: D002460:Cell Line; D002470:Cell Survival; D006801:Humans; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D066329:Protein Aggregates; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D066329:Protein Aggregates; D016875:tau Proteins; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease