Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway
Abstract
Induced protein degradation by PROTACs has emerged as a promising strategy to target nonenzymatic proteins inside the cell. The aim of this study was to identify Keap1, a substrate adaptor protein for ubiquitin E3 ligase involved in oxidative stress regulation, as a novel candidate for PROTACs that can be applied in the degradation of the nonenzymatic protein Tau. A peptide PROTAC by recruiting Keap1-Cul3 ubiquitin E3 ligase was developed and applied in the degradation of intracellular Tau. Peptide 1 showed strong in vitro binding with Keap1 and Tau. With proper cell permeability, peptide 1 was found to colocalize with cellular Keap1 and resulted in the coimmunoprecipitation of Tau and Keap1. The results of flow cytometry and western blotting assays showed that peptide 1 can downregulate the intracellular Tau level in both time- and concentration-dependent manner. The application of Keap1 siRNA silencing and the proteasome inhibitor MG132 confirmed that peptide 1 could promote the Keap1-dependent poly-ubiquitination and proteasome-dependent degradation of Tau. The results suggested that using PROTACs to recruit Keap1 to induce the degradation of Tau may show promising character in the treatment of neurodegenerative disease. Besides, our research demonstrated that Keap1 should be a promising E3 ligase adaptor to be used in the design of novel PROTACs.
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Induced turnover of tau by the UPS, and the degradability of tau species, has been demonstrated by a tau-KEAP1 chimeric peptide PROTAC molecule, as well as by a VHL-tau PROTAC.
“Importantly, induced turnover of tau by the UPS, and the degradability of tau species, has been demonstrated by a tau–kelch-like ECH-associated protein 1 (KEAP1) chimeric peptide PROTAC molecule188, as well as by a VHL–tau PROTAC189.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [188]
Multiple groups have described a range of pepTACs that harness SKP1/SCF F-box, VHL, KEAP1 and other E3 ligases to degrade tau or α-synuclein in primary neurons and other cell lines.
“Additionally, multiple groups have described a range of pepTACs that harness SKP1/SCF F-box, VHL, KEAP1 and other E3 ligases to degrade tau or α-synuclein in primary neurons and other cell lines188,193,213”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [188]
A peptide-based PROTAC that recruits KEAP1 E3 ligase to degrade Tau protein demonstrates the potential of PROTAC technology to treat neurodegenerative disorders such as Alzheimer's disease.
“A peptide-based PROTAC which recruits the KEAP1 E3 ligase to degrade Tau protein demonstrates the potential of PROTAC technology to treat neurodegenerative disorders such as Alzheimer’s disease [73].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [73]
Peptide 1 was able to degrade overexpressed GFP-tagged Tau in different cell lines at 20 μM after 6-12 h of treatment times to various degrees.
“This PROTAC, termed peptide 1, was able to degrade overexpressed GFP-tagged Tau in different cell lines at 20 µM after 6–12 h of treatment times to various degrees.”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [105]
A peptide PROTAC was developed that tethers Keap1 and Tau into a ternary complex.
“Recently, a peptide PROTAC was developed that was able to tether Kelch-like ECH-associated protein-1 (Keap1) and Tau into a ternary complex [105].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [105]
Generation of the full-length peptide decreased Keap1 affinity tenfold and exhibited affinity towards Tau in the sub-micromolar range.
“Generation of the full-length peptide decreased Keap1 affinity tenfold and exhibited affinity towards Tau in the sub-micromolar range.”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [105]
A peptide PROTAC targeting Tau for degradation by KEAP1 provides proof of concept for hijacking BTB E3 ligases.
“Proof of concept for hijacking the BTB E3 ligases has been provided by a peptide PROTAC targeting Tau for degradation by KEAP1 (ref. 79 ).”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [79]
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- Authors
- Lu, M., Liu, T., Jiao, Q., Ji, J., Tao, M., Liu, Y., You, Q., & Jiang, Z.
- Affiliations
- China Pharmaceutical University (CN)
- Corresponding author
- You, Qidong
- Jiang, Zhengyu
- Venue
- European Journal of Medicinal Chemistry
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 146
- Pages
- 251-259
- ISSN
- 0223-5234 (ISSN-L)
- OpenAlex
- W2792069216
- Cited by
- 310
- References
- 45
- Citations by year
- 2026: 30 · 2025: 46 · 2024: 48 · 2023: 47 · 2022: 35 · 2021: 36 · 2020: 37 · 2019: 24 · 2018: 6 · 2014: 1
- FWCI
- 9.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81773581, 81602948, 81773639)
- Natural Science Foundation of Jiangsu Province of China (BK20160746)
- National Major Science and Technology Project of China (2015ZX09101032, 2017ZX09302003, 2017ZX09101-004-003-006)
- Research Innovation Program for College Graduates of Jiangsu Province (KYLX16_1169)
- Priority Academic Program Development of Jiangsu Higher Education Institutions, the Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (SKLNMZZCX201611)
- College Students Innovation Project for the R&D of Novel Drugs (J1310032)
- China Postdoctoral Science Foundation funded project (1600010006)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- PROTACs, Keap1, tau protein, ubiquitination, proteasomal degradation, protein degradation, neurodegenerative diseases, polyubiquitination
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Dose-Response Relationship, Drug, Humans, Peptides, Structure-Activity Relationship, Tumor Cells, Cultured, Molecular Structure, tau Proteins, Proteasome Endopeptidase Complex, Ubiquitination, Drug Discovery
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