Facilitated Tau Degradation by USP14 Aptamers via Enhanced Proteasome Activity.

Abstract

The ubiquitin-proteasome system (UPS) is the primary mechanism by which intracellular proteins, transcription factors, and many proteotoxic proteins with aggregation-prone structures are degraded. The UPS is reportedly downregulated in various neurodegenerative disorders, with increased proteasome activity shown to be beneficial in many related disease models. Proteasomes function under tonic inhibitory conditions, possibly via the ubiquitin chain-trimming function of USP14, a proteasome-associated deubiquitinating enzyme (DUB). We identified three specific RNA aptamers of USP14 (USP14-1, USP14-2, and USP14-3) that inhibited its deubiquitinating activity. The nucleotide sequences of these non-cytotoxic USP14 aptamers contained conserved GGAGG motifs, with G-rich regions upstream, and similar secondary structures. They efficiently elevated proteasomal activity, as determined by the increased degradation of small fluorogenic peptide substrates and physiological polyubiquitinated Sic1 proteins. Additionally, proteasomal degradation of tau proteins was facilitated in the presence of the UPS14 aptamers in vitro. Our results indicate that these novel inhibitory UPS14 aptamers can be used to enhance proteasome activity, and to facilitate the degradation of proteotoxic proteins, thereby protecting cells from various neurodegenerative stressors.

• Authors: Jung Hoon Lee, Seung Kyun Shin, Yanxialei Jiang, Won Hoon Choi, Chaesun Hong, Dong-Eun Kim, Min Jae Lee
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 10757 (Jun 04 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26041011 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aptamers, Nucleotide
• Recombinant Proteins
• USP14 protein, human
• tau Proteins
• Ubiquitin Thiolesterase
• Proteasome Endopeptidase Complex

Topics

• Aptamers, Nucleotide (chemistry, metabolism)
• Base Sequence
• Cell Line
• Cells, Cultured
• Humans
• Nucleic Acid Conformation
• Oxidative Stress
• Proteasome Endopeptidase Complex (metabolism)
• Protein Binding
• Proteolysis
• Recombinant Proteins (genetics, metabolism)
• SELEX Aptamer Technique
• Substrate Specificity
• Ubiquitin Thiolesterase (genetics, metabolism)
• Ubiquitination
• tau Proteins (genetics, metabolism, toxicity)