Abstract
Degrons are pivotal components of the ubiquitin–proteasome system, serving as the recognition determinants through which E3 ubiquitin ligases identify their substrates. Degrons have central roles in both protein quality control and intracellular signalling pathways, and mutations that dysregulate degron activity are associated with a wide range of diseases, including cancer, immunological disorders and neurodegeneration. The number of well-defined degrons remains sparse relative to the ~600 E3 ubiquitin ligases encoded in the human genome. Recent advances in high-throughput degron discovery technologies have accelerated progress in this area, expanding the number of N- and C-terminal degrons, internal degrons and ubiquitin-independent degrons defined experimentally at high resolution. In this Review, we discuss the latest insights into the molecular mechanisms through which degrons act, their functional importance and their relevance in human disease, and consider how bifunctional molecules harness degrons to enable targeted protein degradation for therapeutic benefit.
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Acknowledgements
We thank W. Xu (Harvard), C. Woo (Harvard), E. Shrock and C. Nardone (Harvard Medical School) and members of the Elledge lab for helpful suggestions. Z.Z. is a Croucher Ph.D. Scholar. E.L.M. is supported by a US National Institutes of Health (NIH) K99 award (no. K99AG081456). R.T.T. is a Pemberton-Trinity Fellow and is supported by the European Research Council (ERC-2024-STG 101160971). I.K. is supported by the European Research Council (ERC-2020-STG 947709), the Israel Science Foundation (ISF grant nos. 2380/21 and 3096/21) and the United States–Israel Binational Science Foundation (grant no. 2021029). This work was supported by NIH Aging grant no. AG11085 (to S.J.E.). S.J.E. is a member of the Ludwig Center at Harvard and an Investigator with the Howard Hughes Medical Institute.
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Z.Z., I.K., R.T.T. and E.L.M. wrote the manuscript, supervised by S.J.E. Z.Z. and I.K. prepared the figures with input from S.J.E. All authors discussed, reviewed and edited the manuscript before submission.
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Glossary
- Chaperone
-
A class of proteins that promote folding, assembly, or disassembly of other proteins. They help prevent misfolding and aggregation, especially under stress conditions. In certain contexts, they can promote the degradation of aberrant substrates by recruiting E3s.
- C-terminome stability profiling
-
A systems biology approach to assess the influence of C-terminal sequences on protein stability.
- Global protein stability (GPS)–peptidome system
-
An adaptation of the GPS platform that focuses on measuring the degradation profiles of short peptide sequences to identify degron motifs.
- GPS
-
(Global protein stability). A reporter-based genetic screening method for quantifying the relative stabilities of thousands of proteins in mammalian cells by generating GFP-fusion lentiviral libraries.
- GPT-4
-
A large language model developed by OpenAI, designed to perform advanced natural language processing and reasoning tasks. GPT-4 can synthesize information, extract structured knowledge from unstructured text and assist in the automated curation of biological data, offering new possibilities for accelerating discovery in life sciences.
- Immediate early gene
-
Immediate early genes encode transcription factors from the Fos, EGR and NR4A families. Although the proteins encoded are rapidly and consistently activated across nearly all mammalian cell types, they drive the expression of late-response genes in a cell-type-specific manner, shaping the appropriate response to the initial stimulus.
- Molecular degraders
-
Small molecules that induce selective degradation of target proteins by recruiting them to an E3.
- p97 AAA ATPase
-
A hexameric ATPase that extracts ubiquitinated substrates from membranes or complexes for proteasomal degradation.
- Proteasome
-
The proteasome is a large protein complex responsible for degrading unwanted or damaged proteins tagged with ubiquitin, maintaining protein quality and regulating cellular processes. It consists of a 20S core particle, which carries out proteolysis, and one or two 19S regulatory particles that recognize ubiquitinated proteins, unfold them and feed them into the 20S core for degradation.
- Ribosome quality control
-
A surveillance pathway that detects and resolves stalled ribosomes. It ensures the degradation of incomplete nascent polypeptides and the recycling of ribosomal subunits to maintain translation fidelity and protein homeostasis.
- Thalidomide class of drugs
-
Immunomodulatory imide drugs, including thalidomide, lenalidomide and pomalidomide, act as molecular glues by promoting neosubstrate recognition by the CUL4CRBN E3 complex.
- Ubiquilin
-
A family of ubiquitin-like (Ubl) and ubiquitin-associated (Uba) domain-containing adaptor proteins that can target proteins to the proteasome for both ubiquitin-dependent and ubiquitin-independent degradation.
- Ubiquitin-like (Ubl) domain
-
Ubiquitin-like (Ubl) domains are protein domains that share structural similarity with ubiquitin. Small proteins such as SUMO, NEDD8 and FAT10 are composed mainly of a Ubl domain and can be covalently conjugated to target proteins, thereby modifying their stability, activity or localization; larger proteins such as the ubiquilins contain a Ubl domain in addition to other protein domains, with the Ubl domain thought to enable interactions with the proteasome or other cellular machinery.
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Zhang, Z., Mena, E.L., Timms, R.T. et al. Degrons: defining the rules of protein degradation. Nat Rev Mol Cell Biol (2025). https://doi.org/10.1038/s41580-025-00870-z
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DOI: https://doi.org/10.1038/s41580-025-00870-z
