The AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system
Open accessAbstract
Targeted protein degradation allows targeting undruggable proteins for therapeutic applications as well as eliminating proteins of interest for research purposes. While several degraders that harness the proteasome or the lysosome have been developed, a technology that simultaneously degrades targets and accelerates cellular autophagic flux is still missing. In this study, we develop a general chemical tool and platform technology termed AUTOphagy-TArgeting Chimera (AUTOTAC), which employs bifunctional molecules composed of target-binding ligands linked to autophagy-targeting ligands. AUTOTACs bind the ZZ domain of the otherwise dormant autophagy receptor p62/Sequestosome-1/SQSTM1, which is activated into oligomeric bodies in complex with targets for their sequestration and degradation. We use AUTOTACs to degrade various oncoproteins and degradation-resistant aggregates in neurodegeneration at nanomolar DC 50 values in vitro and in vivo. AUTOTAC provides a platform for selective proteolysis in basic research and drug development.
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AUTOTAC PBA-1105 (232) provokes autophagic degradation of TauP310L with approximately 1-10 nM DC50; in a transgenic mouse model treated with 20 or 50 mg kg−1 PBA-1105 injections thrice weekly for one month, significant clearance of TauP301L aggregates was observed, indicating that blood-brain barrier penetration was not a constraint.
“AUTOTAC PBA-1105 (232) provokes autophagic degradation of TauP310L with remarkable efficacy at approximately 1–10 nM DC50 (Table 4). In a transgenic mouse model treated with 20 or 50 mg kg−1 PBA-1105 injections thrice weekly for one month, significant clearance of TauP301L aggregates was observed, indicating that blood-brain barrier penetration was not a constraint.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [541]
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Cites
Lysosome-targeting chimaeras for degradation of extracellular proteins
Banik, S. M., Pedram, K., Wisnovsky, S., Ahn, G., Riley, N. M., & Bertozzi, C. R. (2020) · Nature · doi:10.1038/s41586-020-2545-9 · Cited by 1,199 · see citing works
Proteasomal and Autophagic Degradation Systems
Đikić, I. (2017) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061516-044908 · Cited by 1,165 · see citing works
Autophagy at the crossroads of catabolism and anabolism
Kaur, J., & Debnath, J. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm4024 · Cited by 993 · see citing works
Targeted protein degradation: expanding the toolbox
Schapira, M., Calabrese, M. F., Bullock, A. N., & Crews, C. M. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0047-y · Cited by 960 · see citing works
Degradation of misfolded proteins in neurodegenerative diseases: Therapeutic targets and strategies
Ciechanover, A., & Kwon, Y. T. (2015) · Experimental & Molecular Medicine · doi:10.1038/emm.2014.117 · Cited by 898 · see citing works
Self-citationPROteolysis TArgeting Chimeras (PROTACs) — Past, present and future
Pettersson, M., & Crews, C. M. (2019) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2019.01.002 · Cited by 818 · see citing works
AUTACs: Cargo-Specific Degraders Using Selective Autophagy
Takahashi, D., Moriyama, J., Nakamura, T., Miki, E., Takahashi, E., Sato, A., Akaike, T., Itto-Nakama, K., & Arimoto, H. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.09.009 · Cited by 675 · see citing works
Cleaning house: selective autophagy of organelles
Anding, A. L., & Baehrecke, E. H. (2017) · Developmental Cell · doi:10.1016/j.devcel.2017.02.016 · Cited by 576 · see citing works
Allele-selective lowering of mutant HTT protein by HTT–LC3 linker compounds
Li, Z., Wang, C., Wang, Z., Zhu, C., Li, J., Sha, T., Ma, L., Gao, C., Yang, Y., Sun, Y., et al. (2019) · Nature · doi:10.1038/s41586-019-1722-1 · Cited by 551 · see citing works
N-degron and C-degron pathways of protein degradation
Varshavsky, A. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1816596116 · Cited by 544 · see citing works
Choosing the Right Tool for the Job: RNAi, TALEN, or CRISPR
Boettcher, M., & McManus, M. T. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.04.028 · Cited by 510 · see citing works
Wagner, J., Ryazanov, S., Leonov, A., Levin, J., Shi, S., Schmidt, F., Prix, C., Pan-Montojo, F. J., Bertsch, U., Mitteregger-Kretzschmar, G., et al. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1114-9 · Cited by 457 · see citing works
A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers
Thibaudeau, T. A., Anderson, R. T., & Smith, D. M. (2018) · Nature Communications · doi:10.1038/s41467-018-03509-0 · Cited by 356 · see citing works
Hu, J., Hu, B., Wang, M., Xu, F., Miao, B., Yang, C., Wang, M., Liu, Z., Hayes, D. F., Chinnaswamy, K., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01572 · Cited by 286 · see citing works
Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models
Silva, M. C., Ferguson, F. M., Cai, Q., Donovan, K. A., Nandi, G., Patnaik, D., Zhang, T., Huang, H.-T., Lucente, D. E., Dickerson, B. C., et al. (2019) · eLife · doi:10.7554/elife.45457 · Cited by 283 · see citing works
The therapeutic potential of chemical chaperones in protein folding diseases
Cortez, L. M., & Sim, V. L. (2014) · Prion · doi:10.4161/pri.28938 · Cited by 254 · see citing works
Cha‐Molstad, H., Yu, J. E., Feng, Z., Lee, S. H., Kim, J. G., Yang, P., Han, B., Sung, K. W., Yoo, Y. D., Hwang, J., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00085-7 · Cited by 246 · see citing works
Self-citationDegradation of lipid droplets by chimeric autophagy-tethering compounds
Fu, Y., Chen, N., Wang, Z., Luo, S., Ding, Y., & Lu, B. (2021) · Cell Research · doi:10.1038/s41422-021-00532-7 · Cited by 232 · see citing works
Protein aggregation and degradation mechanisms in neurodegenerative diseases.
Takalo, M., Salminen, A., Soininen, H. S., Hiltunen, M. O., & Haapasalo, A. (2013) · Europe PMC (PubMed Central) · Cited by 219 · see citing works
The importance of regulatory ubiquitination in cancer and metastasis
Gallo, L. H., Ko, J., & Donoghue, D. J. (2017) · Cell Cycle · doi:10.1080/15384101.2017.1288326 · Cited by 171 · see citing works
The N-Degron Pathway Mediates ER-phagy
Ji, C. H., Kim, H. Y., Heo, A. J., Lee, S. H., Lee, M. J., Kim, S., Srinivasrao, G., Mun, S. R., Cha‐Molstad, H., Ciechanover, A. J., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.06.028 · Cited by 162 · see citing works
Self-citationGhag, G., Bhatt, N. N., Cantu, D. V., Guerrero‐Munoz, M. J., Ellsworth, A., Sengupta, U., & Kayed, R. (2018) · Protein Science · doi:10.1002/pro.3499 · Cited by 157 · see citing works
Strang, K. H., Croft, C. L., Sorrentino, Z. A., Chakrabarty, P., Golde, T. E., & Giasson, B. I. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.815357 · Cited by 144 · see citing works
RNA editing in the forefront of epitranscriptomics and human health
Christofi, T., & Zaravinos, A. (2019) · Journal of Translational Medicine · doi:10.1186/s12967-019-2071-4 · Cited by 139 · see citing works
Protein misfolding disorders and macroautophagy
Menzies, F. M., Moreau, K., & Rubinsztein, D. C. (2011) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2010.10.010 · Cited by 129 · see citing works
Targeted protein degradation and the enzymology of degraders
Fisher, S. L., & Phillips, A. J. (2018) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2018.05.004 · Cited by 126 · see citing works
Heras‐Garvin, A., Weckbecker, D., Ryazanov, S., Leonov, A., Griesinger, C., Giese, A., Wenning, G. K., & Stefanova, N. (2018) · Movement Disorders · doi:10.1002/mds.27562 · Cited by 120 · see citing works
Development of Small Molecule Chimeras That Recruit AhR E3 Ligase to Target Proteins
Ohoka, N., Tsuji, G., Shoda, T., Fujisato, T., Kurihara, M., Demizu, Y., & Naito, M. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.9b00704 · Cited by 117 · see citing works
Tau binding protein CAPON induces tau aggregation and neurodegeneration
Hashimoto, S., Matsuba, Y., Kamano, N., Mihira, N., Sahara, N., Takano, J., Muramatsu, S.-I., Saido, T. C., & Saito, T. (2019) · Nature Communications · doi:10.1038/s41467-019-10278-x · Cited by 111 · see citing works
Ding, J., Yeh, C., Sun, Y., Lin, C.-Y., Chou, J., Ou, Z., Chang, C., Qi, J., & Yeh, S. (2018) · Oncogene · doi:10.1038/s41388-018-0175-6 · Cited by 107 · see citing works
Advances in targeted degradation of endogenous proteins
Röth, S., Fulcher, L. J., & Sapkota, G. P. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03112-6 · Cited by 92 · see citing works
N-terminal arginylation generates a bimodal degron that modulates autophagic proteolysis
Yoo, Y. D., Mun, S. R., Ji, C. H., Sung, K. W., Kang, K. Y., Heo, A. J., Lee, S. H., An, J. Y., Hwang, J., Xie, X., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1719110115 · Cited by 86 · see citing works
Self-citationA novel nickel complex works as a proteasomal deubiquitinase inhibitor for cancer therapy
Zhao, C., Chen, X., Zang, D., Lan, X., Liao, S., Yang, C., Zhang, P., Wu, J., Li, X., Liu, N., et al. (2016) · Oncogene · doi:10.1038/onc.2016.114 · Cited by 62 · see citing works
Salomon, P. L., Reid, E. E., Archer, K. E., Harris, L., Maloney, E. K., Wilhelm, A. J., Miller, M. L., Chari, R. V. J., Keating, T. A., & Singh, R. (2019) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.9b00696 · Cited by 51 · see citing works
Dalal, K., Ban, F., Li, H., Morin, H., Roshan‐Moniri, M., Tam, K. J., Shepherd, A., Sharma, A., Peacock, J. W., Carlson, M. L., et al. (2018) · Cancer Letters · doi:10.1016/j.canlet.2018.08.016 · Cited by 50 · see citing works
Galli, C. L., Sensi, C., Fumagalli, A., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0104822 · Cited by 48 · see citing works
Chemically Induced Cellular Proteolysis: An Emerging Therapeutic Strategy for Undruggable Targets.
Moon, S., & Lee, B. (2018) · Europe PMC (PubMed Central) · doi:10.14348/molcells.2018.0372 · Cited by 45 · see citing works
Kubánek, M., Schimerová, T., Piherová, L., et al. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9040937 · Cited by 44 · see citing works
Heinrich, T., Seenisamy, J., Blume, B., Bomke, J., Calderini, M., Eckert, U., Friese‐Hamim, M., Kohl, R., Lehmann, M., Leuthner, B., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00041 · Cited by 30 · see citing works
Shin, S., Kim, D., Song, J. Y., Jeong, H., Hyeon, S. J., Kowall, N. W., Ryu, H., Pae, A. N., Lim, S., & Kim, Y. K. (2020) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2020.101782 · Cited by 29 · see citing works
Self-citationSelective oestrogen receptor antagonists inhibit oesophageal cancer cell proliferation in vitro
Al‐Khyatt, W., Tufarelli, C., Khan, R. N., et al. (2018) · BMC Cancer · doi:10.1186/s12885-018-4030-5 · Cited by 27 · see citing works
Musil, D., Heinrich, T., & Lehmann, M. (2019) · Worldwide Protein Data Bank · doi:10.2210/pdb6qej/pdb · Cited by 17 · see citing works
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Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
Tau-targeting therapies for Alzheimer disease: Current status and future directions
Congdon, E. E., Ji, C., Tetlow, A. M., Jiang, Y., & Sigurdsson, E. M. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00883-2 · Cited by 371 · see citing works
Chasing molecular glue degraders: screening approaches
Domostegui, A., Nieto-Barrado, L., Perez-Lopez, C., & Mayor-Ruiz, C. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00197g · Cited by 200 · see citing works
A New Wave of Targeting ‘Undruggable’ Wnt Signaling for Cancer Therapy: Challenges and Opportunities
Park, W.-J., & Kim, M. J. (2023) · Cells · doi:10.3390/cells12081110 · Cited by 57 · see citing works
Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence
Duran-Frigola, M., Cigler, M., & Winter, G. E. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.2c11098 · Cited by 50 · see citing works
Application of Novel Degraders Employing Autophagy for Expediting Medicinal Research
Li, X., Liu, Q., Xie, X., Peng, C., Pang, Q., Liu, B., & Han, B. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01712 · Cited by 46 · see citing works
Targeted protein modification as a paradigm shift in drug discovery
Amirian, R., Azadi Badrbani, M., Izadi, Z., Samadian, H., Bahrami, G., Sarvari, S., Abdolmaleki, S., Nabavi, S. M., Derakhshankhah, H., & Jaymand, M. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115765 · Cited by 18 · see citing works
- Authors
- Ji, C. H., Kim, H. Y., Lee, M. J., Heo, A. J., Park, D. Y., Lim, S., Shin, S., Ganipisetti, S., Yang, W. S., Jung, C. A., Kim, K. Y., Jeong, E. H., Park, S. H., Bin Kim, S., Lee, S. J., Na, J. E., Kang, J. I., Chi, H. M., Kim, H. T., Kim, Y. K., Kim, B. Y., & Kwon, Y. T.
- Affiliations
- Seoul National University (KR)
- Korea Institute of Science and Technology (KR)
- University of Louisville (US)
- Korea Research Institute of Bioscience and Biotechnology (KR)
- Pohang University of Science and Technology (KR)
- Corresponding author
- Kim, Hee Yeon
- Kim, Hyun Tae
- Kim, Yun Kyung
- Kim, Bo Yeon
- Kwon, Yong Tae
- ORCID
- Venue
- Nature Communications
- Published
- 2022-02-16
- Volume
- 13
- Issue
- 1
- Pages
- 904-904
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8850458
- OpenAlex
- W4213121119
- Cited by
- 350
- References
- 42
- Citations by year
- 2026: 86 · 2025: 95 · 2024: 78 · 2023: 61 · 2022: 28 · 2014: 1
- FWCI
- 21.63
- Type
- journal article
- Language
- en
- Update notices
- correction (2022-04-12)
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Ministry of Science, ICT and Future Planning (HU21C0201, NRF-2016R1A2B3011389, NRF-2021R1A2B5B03002614, NRF-2020R1A5A1019023)
- National Research Council of Science and Technology (CAP-16-03-KRIBB)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- targeted protein degradation, autophagy-lysosome system, p62, ZZ domain, bifunctional degraders, autophagy receptors, oncoprotein degradation, neurodegeneration, protein aggregates, selective proteolysis
- MeSH terms
- Proteostasis, Autophagy, HeLa Cells, Humans, Lysosomes, Protein Binding, Signal Transduction, Oncogene Proteins, Protein Folding, Cell Line, Tumor, Proteolysis, Protein Aggregates
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