Cited by 544Ubiquitin and proteasome pathwaysProtein Degradation and InhibitorsAutophagy in Disease and Therapy

The DOI matches its Crossref record; 82 of the 82 references it cites were found in a registry or an index.

N-degron and C-degron pathways of protein degradation

Open access

Varshavsky, Alexander·2019·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1816596116PMC PMC6329975

Open this paper in CoChat — free account Open PDF

Abstract

This perspective is partly review and partly proposal. N-degrons and C-degrons are degradation signals whose main determinants are, respectively, the N-terminal and C-terminal residues of cellular proteins. N-degrons and C-degrons include, to varying extents, adjoining sequence motifs, and also internal lysine residues that function as polyubiquitylation sites. Discovered in 1986, N-degrons were the first degradation signals in short-lived proteins. A particularly large set of C-degrons was discovered in 2018. We describe multifunctional proteolytic systems that target N-degrons and C-degrons. We also propose to denote these systems as “N-degron pathways” and “C-degron pathways.” The former notation replaces the earlier name “N-end rule pathways.” The term “N-end rule” was introduced 33 years ago, when only some N-terminal residues were thought to be destabilizing. However, studies over the last three decades have shown that all 20 amino acids of the genetic code can act, in cognate sequence contexts, as destabilizing N-terminal residues. Advantages of the proposed terms include their brevity and semantic uniformity for N-degrons and C-degrons. In addition to being topologically analogous, N-degrons and C-degrons are related functionally. A proteolytic cleavage of a subunit in a multisubunit complex can create, at the same time, an N-degron (in a C-terminal fragment) and a spatially adjacent C-degron (in an N-terminal fragment). Consequently, both fragments of a subunit can be selectively destroyed through attacks by the N-degron and C-degron pathways.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1073/pnas.1816596116

Cites

82 of 82 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

In Vivo Half-Life of a Protein Is a Function of Its Amino-Terminal Residue
Bachmair, A., Finley, D. J., & Varshavsky, A. J. (1986) · Science · doi:10.1126/science.3018930 · Cited by 1,976
Self-citation
Ubiquitin ligases: structure, function, and regulation
Zheng, N., & Shabek, N. (2017) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060815-014922 · Cited by 1,499
In vivo aspects of protein folding and quality control
Balchin, D., Hayer-Hartl, M. K., & Hartl, F. U. (2016) · Science · doi:10.1126/science.aac4354 · Cited by 1,477
Role of a peptide tagging system in degradation of proteins synthesized from damaged messenger RNA
Keiler, K. C., Waller, P. R. H., & Sauer, R. T. (1996) · Science · doi:10.1126/science.271.5251.990 · Cited by 1,125
The logic of the 26S proteasome.
Collins, G. A., & Goldberg, A. L. (2017) · Cell · doi:10.1016/j.cell.2017.04.023 · Cited by 933
Structure and Function of the 26S Proteasome
Bard, J. A. M., Goodall, E. A., Greene, E. R., Jönsson, E., Dong, K. C., & Martin, A. (2018) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-062917-011931 · Cited by 867
The N‐end rule pathway and regulation by proteolysis
Varshavsky, A. J. (2011) · Protein Science · doi:10.1002/pro.666 · Cited by 721
Self-citation
The ubiquitin system
Hershko, A., Ciechanover, A. J., & Varshavsky, A. J. (2000) · Nature Medicine · doi:10.1038/80384 · Cited by 661
Self-citation
N-Terminal Acetylation of Cellular Proteins Creates Specific Degradation Signals
Hwang, C.-S., Shemorry, A., & Varshavsky, A. (2010) · Science · doi:10.1126/science.1183147 · Cited by 650
Self-citation
Ubiquitylation at the crossroads of development and disease
Rapé, M. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.83 · Cited by 621

Show all 82 references

Sorted by citations

Targeted protein degradation: elements of PROTAC design
Paiva, S.-L., & Crews, C. M. (2019) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2019.02.022 · Cited by 598
The IMG/M data management and analysis system v.6.0: new tools and advanced capabilities
Chen, I.-M. A., Chu, K., Palaniappan, K., Ratner, A., Huang, J., Huntemann, M., Hajek, P. P., Ritter, S., Varghese, N. J., Seshadri, R., et al. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa939 · Cited by 433
Redox regulation: mechanisms, biology and therapeutic targets in diseases
Li, B., Ming, H., Qin, S., Nice, E. C., Dong, J., Du, Z., & Huang, C. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02095-6 · Cited by 389
The AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system
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., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28520-4 · Cited by 350
Proteomic and interactomic insights into the molecular basis of cell functional diversity
Bludau, I., & Aebersold, R. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0231-2 · Cited by 297
Co-translational, Post-translational, and Non-catalytic Roles of N-Terminal Acetyltransferases
Aksnes, H., Ree, R., & Arnesen, T. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.02.007 · Cited by 258
A glycine-specific N-degron pathway mediates the quality control of protein N -myristoylation
Timms, R. T., Zhang, Z., Rhee, D. Y., Harper, J. W., Koren, I., & Elledge, S. J. (2019) · Science · doi:10.1126/science.aaw4912 · Cited by 244
The Scope, Functions, and Dynamics of Posttranslational Protein Modifications
Millar, A. H., Heazlewood, J. L., Giglione, C., Holdsworth, M. J., Bachmair, A., & Schulze, W. X. (2019) · Annual Review of Plant Biology · doi:10.1146/annurev-arplant-050718-100211 · Cited by 240
An apical hypoxic niche sets the pace of shoot meristem activity
Weits, D. A., Kunkowska, A. B., Kamps, N. C. W., Portz, K., Packbier, N. K., Venza, Z. N., Gaillochet, C., Lohmann, J. U., Pedersen, O., van Dongen, J. T., et al. (2019) · Nature · doi:10.1038/s41586-019-1203-6 · Cited by 234
Conserved N-terminal cysteine dioxygenases transduce responses to hypoxia in animals and plants
Masson, N., Keeley, T. P., Giuntoli, B., White, M. D., Lavilla-Puerta, M., Pierdomenico Perata, A., Hopkinson, R. J., Flashman, E., Licausi, F., & Ratcliffe, P. J. (2019) · Science · doi:10.1126/science.aaw0112 · Cited by 231
Enteroviral 3C protease activates the human NLRP1 inflammasome in airway epithelia
Robinson, K. S., Teo, D. E. T., Tan, K. S., Toh, G. A., Ong, H. H., Lim, C., Lay, K., Au, B. V., Lew, T. S., Chu, J. J. H., et al. (2020) · Science · doi:10.1126/science.aay2002 · Cited by 222
Prey for the Proteasome: Targeted Protein Degradation—A Medicinal Chemist's Perspective
Luh, L. M., Scheib, U., Juenemann, K., Wortmann, L., Brands, M., & Cromm, P. M. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.202004310 · Cited by 201
The roles of E3 ubiquitin ligases in cancer progression and targeted therapy
Sampson, C., Wang, Q., Otkur, W., Zhao, H., Lu, Y., Liu, X., & Piao, H. (2023) · Clinical and Translational Medicine · doi:10.1002/ctm2.1204 · Cited by 193
ELM—the Eukaryotic Linear Motif resource—2024 update
Kumar, M., Michael, S., Alvarado-Valverde, J., Zeke, A., Lázár, T., Glavina, J., Nagy‐Kanta, E., Donagh, J. M., Kálmán, Z. E., Pascarelli, S., et al. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad1058 · Cited by 185
The NLRP1 inflammasome: new mechanistic insights and unresolved mysteries
Mitchell, P. S., Sandstrom, A., & Vance, R. E. (2019) · Current Opinion in Immunology · doi:10.1016/j.coi.2019.04.015 · Cited by 178
ER‐phagy: selective autophagy of the endoplasmic reticulum
Mochida, K., & Nakatogawa, H. (2022) · EMBO Reports · doi:10.15252/embr.202255192 · Cited by 181
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 166
The midnolin-proteasome pathway catches proteins for ubiquitination-independent degradation
Gu, X., Nardone, C., Kamitaki, N., Mao, A., Elledge, S. J., & Greenberg, M. E. (2023) · Science · doi:10.1126/science.adh5021 · Cited by 161
An E3 ligase guide to the galaxy of small-molecule-induced protein degradation
Jevtić, P., Haakonsen, D. L., & Rapé, M. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.04.002 · Cited by 149
Molecular oxygen as a signaling component in plant development
Weits, D. A., van Dongen, J. T., & Licausi, F. (2020) · New Phytologist · doi:10.1111/nph.16424 · Cited by 138
Driving E3 Ligase Substrate Specificity for Targeted Protein Degradation: Lessons from Nature and the Laboratory
Cowan, A. D., & Ciulli, A. (2022) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-032620-104421 · Cited by 136
How the ends signal the end: Regulation by E3 ubiquitin ligases recognizing protein termini
Sherpa, D., Chrustowicz, J., & Schulman, B. A. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.02.004 · Cited by 124
Oxygen-sensing mechanisms across eukaryotic kingdoms and their roles in complex multicellularity
Hammarlund, E. U., Flashman, E., Mohlin, S., & Licausi, F. (2020) · Science · doi:10.1126/science.aba3512 · Cited by 120
The ins and outs of Bacillus proteases: activities, functions and commercial significance
Harwood, C. R., & Kikuchi, Y. (2021) · FEMS Microbiology Reviews · doi:10.1093/femsre/fuab046 · Cited by 116
Amidase as a versatile tool in amide-bond cleavage: From molecular features to biotechnological applications
Wu, Z., Liu, C., Zhang, Z., Zheng, R., & Zheng, Y. (2020) · Biotechnology Advances · doi:10.1016/j.biotechadv.2020.107574 · Cited by 116
Protein lipidation in health and disease: molecular basis, physiological function and pathological implication
Yuan, Y., Li, P., Li, J., Zhao, Q., Chang, Y., & He, X. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01759-7 · Cited by 118
Squalene monooxygenase: a journey to the heart of cholesterol synthesis
Chua, N. K., Coates, H. W., & Brown, A. J. (2020) · Progress in Lipid Research · doi:10.1016/j.plipres.2020.101033 · Cited by 112
Protein Quality Control and Lipid Droplet Metabolism
Roberts, M. A., & Olzmann, J. A. (2020) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-031320-101827 · Cited by 112
Targeted protein degradation directly engaging lysosomes or proteasomes
Kim, J., Byun, I., Kim, D. Y., Joh, H., Kim, H. J., & Lee, M. J. (2024) · Chemical Society Reviews · doi:10.1039/d3cs00344b · Cited by 108
Tying up loose ends: the N-degron and C-degron pathways of protein degradation
Timms, R. T., & Koren, I. (2020) · Biochemical Society Transactions · doi:10.1042/bst20191094 · Cited by 100
Arabidopsis phenotyping reveals the importance of alcohol dehydrogenase and pyruvate decarboxylase for aerobic plant growth
Ventura, I., Brunello, L., Iacopino, S., Valeri, M. C., Novi, G., Dornbusch, T., Pierdomenico Perata, A., & Loreti, E. (2020) · Scientific Reports · doi:10.1038/s41598-020-73704-x · Cited by 99
Calcium-dependent activation of CPK12 facilitates its cytoplasm-to-nucleus translocation to potentiate plant hypoxia sensing by phosphorylating ERF-VII transcription factors
Fan, B., Liao, K., Wang, L., Shi, L., Zhang, Y., Xu, L., Zhou, Y., Li, J., Chen, Y., Chen, Q., et al. (2023) · Molecular Plant · doi:10.1016/j.molp.2023.04.002 · Cited by 98
The MARCHF6 E3 ubiquitin ligase acts as an NADPH sensor for the regulation of ferroptosis
Nguyen, K. T., Mun, S.-H., Yang, J., Lee, J., Seok, O.-H., Kim, E., Kim, D., An, S. Y., Seo, D.-Y., Suh, J.-Y., et al. (2022) · Nature Cell Biology · doi:10.1038/s41556-022-00973-1 · Cited by 92
Interconversion between Anticipatory and Active GID E3 Ubiquitin Ligase Conformations via Metabolically Driven Substrate Receptor Assembly
Qiao, S., Langlois, C., Chrustowicz, J., Sherpa, D., Karayel, Ö., Hansen, F. M., Beier, V., von Gronau, S., Bollschweiler, D., Schäfer, T., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.10.009 · Cited by 93
High-resolution snapshots of human N-myristoyltransferase in action illuminate a mechanism promoting N-terminal Lys and Gly myristoylation
Dian, C., Pérez‐Dorado, I., Rivière, F., Asensio, T., Legrand, P., Ritzefeld, M., Shen, M., Cota, E., Meinnel, T., Tate, E. W., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-14847-3 · Cited by 92
Post-translational Modifications of the Protein Termini
Chen, L., & Kashina, A. S. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.719590 · Cited by 89
The logic of protein post‐translational modifications (PTMs): Chemistry, mechanisms and evolution of protein regulation through covalent attachments
Suskiewicz, M. J. (2024) · BioEssays · doi:10.1002/bies.202300178 · Cited by 91
N-terminal acetylation shields proteins from degradation and promotes age-dependent motility and longevity
Varland, S., Silva, R. D., Kjosås, I., Faustino, A., Bogaert, A., Billmann, M., Boukhatmi, H., Kellen, B., Costanzo, M., Drazic, A., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-42342-y · Cited by 85
The plant N‐degron pathways of ubiquitin‐mediated proteolysis
Holdsworth, M. J., Vicente, J., Sharma, G., Abbas, M., & Zubrycka, A. (2019) · Journal of Integrative Plant Biology · doi:10.1111/jipb.12882 · Cited by 86
Ubiquitination in the ERAD Process
Lopata, A., Kniss, A., Löhr, F., Rogov, V. V., & Dötsch, V. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21155369 · Cited by 85
Mechanisms of readthrough mitigation reveal principles of GCN1-mediated translational quality control
Müller, M. B. D., Kasturi, P., Jayaraj, G. G., & Hartl, F. U. (2023) · Cell · doi:10.1016/j.cell.2023.05.035 · Cited by 83
Structure, function, and substrates of Clp AAA+ protease systems in cyanobacteria, plastids, and apicoplasts: A comparative analysis
Bouchnak, I., & van Wijk, K. J. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100338 · Cited by 77
Convergence of mammalian RQC and C-end rule proteolytic pathways via alanine tailing
Thrun, A., Garzia, A., Kigoshi-Tansho, Y., Patil, P. R., Umbaugh, C. S., Dallinger, T., Liu, J., Kreger, S., Patrizi, A., Cox, G. A., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.03.004 · Cited by 77
Recent structural insights into the mechanism of ClpP protease regulation by AAA+ chaperones and small molecules
Mabanglo, M. F., & Houry, W. A. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101781 · Cited by 77
CRISPR/Cas9-based split homing gene drive targeting doublesex for population suppression of the global fruit pest Drosophila suzukii
Yadav, A. K., Butler, C. D., Ah, Y., Patil, A. A., Lloyd, A. L., & Scott, M. J. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2301525120 · Cited by 80
Mitochondrial matrix proteases: quality control and beyond
Szczepanowska, K., & Trifunović, A. (2021) · FEBS Journal · doi:10.1111/febs.15964 · Cited by 78
Conditional Protein Function via N-Degron Pathway–Mediated Proteostasis in Stress Physiology
Dißmeyer, N. (2019) · Annual Review of Plant Biology · doi:10.1146/annurev-arplant-050718-095937 · Cited by 76
N-degron pathways
Varshavsky, A. J. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2408697121 · Cited by 75
Self-citation
Measuring ROS and redox markers in plant cells
Akter, M. S., Khan, M. S., Smith, E. N., & Flashman, E. (2021) · RSC Chemical Biology · doi:10.1039/d1cb00071c · Cited by 70
The ubiquitin–proteasome system links NADPH metabolism to ferroptosis
Yang, J., Lee, Y., & Hwang, C. (2023) · Trends in Cell Biology · doi:10.1016/j.tcb.2023.07.003 · Cited by 69
Gid10 as an alternative N-recognin of the Pro/N-degron pathway
Melnykov, A., Chen, S., & Varshavsky, A. J. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1908304116 · Cited by 67
Self-citation
E3 Ubiquitin Ligase TRIP12: Regulation, Structure, and Physiopathological Functions
Brunet, M., Vargas, C., Larrieu, D., Torrisani, J., & Dufresne, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228515 · Cited by 72
Molecular glue-mediated targeted protein degradation: A novel strategy in small-molecule drug development
Tan, X., Huang, Z., Pei, H., Jia, Z., & Zheng, J. (2024) · iScience · doi:10.1016/j.isci.2024.110712 · Cited by 66
Chemical modulation of SQSTM1/p62-mediated xenophagy that targets a broad range of pathogenic bacteria
Lee, Y. J., Kim, J. K., Jung, C. H., Kim, Y. J., Jung, E. J., Lee, S. H., Choi, H. R., Son, Y. S., Shim, S. M., Jeon, S. M., et al. (2022) · Autophagy · doi:10.1080/15548627.2022.2054240 · Cited by 67
The calcium-dependent protein kinase CPK16 regulates hypoxia-induced ROS production by phosphorylating the NADPH oxidase RBOHD in Arabidopsis
Yu, W.-W., Chen, Q., Liao, K., Zhou, D., Yang, Y., He, M., Yu, L., Guo, D.-Y., Xiao, S., Xie, R., et al. (2024) · The Plant Cell · doi:10.1093/plcell/koae153 · Cited by 65
The N-terminal cysteine is a dual sensor of oxygen and oxidative stress
Heo, A. J., Kim, S., Ji, C. H., Han, D., Lee, S. J., Lee, S. H., Lee, M. J., Lee, J. S., Ciechanover, A. J., Kim, B. Y., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2107993118 · Cited by 64
Cotranslational N-degron masking by acetylation promotes proteome stability in plants
Linster, E., Ruiz, F. L. F., Miklánková, P., Ruppert, T., Müller, J., Armbruster, L., Gong, X., Serino, G., Mann, M., Hell, R., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28414-5 · Cited by 64
Roles of E3 Ubiquitin Ligases in Plant Responses to Abiotic Stresses
Wang, S., Lv, X., Zhang, J., Chen, D., Chen, S., Fan, G., Ma, C., & Wang, Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23042308 · Cited by 65
Nrf2 in Cancer, Detoxifying Enzymes and Cell Death Programs
Jenkins, T., & Gouge, J. (2021) · Antioxidants · doi:10.3390/antiox10071030 · Cited by 65
Building ubiquitination machineries: E3 ligase multi-subunit assembly and substrate targeting by PROTACs and molecular glues
Ramachandran, S., & Ciulli, A. (2020) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2020.10.009 · Cited by 62
Amelioration of hepatic steatosis by dietary essential amino acid-induced ubiquitination
Zhang, Y., Lin, S., Peng, J., Liang, X., Yang, Q., Bai, X., Li, Y., Li, J., Dong, W., Wang, Y., et al. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.01.021 · Cited by 59
Molecular basis for arginine C-terminal degron recognition by Cul2FEM1 E3 ligase
Chen, X., Liao, S., Makaros, Y., Guo, Q., Zhu, Z., Krizelman, R., Dahan, K., Tu, X., Yao, X., Koren, I., et al. (2021) · Nature Chemical Biology · doi:10.1038/s41589-020-00704-3 · Cited by 58
Current advances of small molecule E3 ligands for proteolysis-targeting chimeras design
Mi, D., Li, Y., Gu, H., Li, Y., & Chen, Y. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115444 · Cited by 58
Degrons: defining the rules of protein degradation
Zhang, Z., Mena, E. L., Timms, R. T., Koren, I., & Elledge, S. J. (2025) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-025-00870-z · Cited by 67
Epstein-Barr virus BNRF1 destabilizes SMC5/6 cohesin complexes to evade its restriction of replication compartments
Yiu, S. P. T., Guo, R., Zerbe, C. M., Weekes, M. P., & Gewurz, B. E. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110411 · Cited by 57
Recognition of nonproline N-terminal residues by the Pro/N-degron pathway
Cheng, D., Chen, S., Melnykov, A., Weirich, S., Sun, K., Jeltsch, A., Varshavsky, A. J., & Min, J. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2007085117 · Cited by 55
Self-citation
Optimization of CAR-T Cell-Based Therapies Using Small-Molecule-Based Safety Switches
Zheng, Y., Nandakumar, K. S., & Cheng, K. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c02054 · Cited by 55
Targeted Degradation of Transcription Coactivator SRC‐1 through the N‐Degron Pathway
Lee, Y., Heo, J., Jeong, H., Hong, K. T., Kwon, D. H., Shin, M. H., Oh, M., Sable, G. A., Ahn, G., Lee, J., et al. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.202005004 · Cited by 53
Timer-based proteomic profiling of the ubiquitin-proteasome system reveals a substrate receptor of the GID ubiquitin ligase
Kong, K.-Y. E., Fischer, B. M., Meurer, M., Kats, I., Li, Z., Rühle, F., Barry, J. D., Kirrmaier, D., Chevyreva, V., Luis, B.-J. S., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.04.018 · Cited by 56
The Cys/N-degron pathway in the ubiquitin–proteasome system and autophagy
Heo, A. J., Ji, C. H., & Kwon, Y. T. (2022) · Trends in Cell Biology · doi:10.1016/j.tcb.2022.07.005 · Cited by 56
Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): the Possible Contribution of Immune Dysregulation to Disease Pathogenesis
Ebstein, F., Küry, S., Papendorf, J. J., & Krüger, E. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.733012 · Cited by 53
A central role for regulated protein stability in the control of TFE3 and MITF by nutrients
Nardone, C., Palanski, B. A., Scott, D. C., Timms, R. T., Barber, K. W., Gu, X., Mao, A., Leng, Y., Watson, E. V., Schulman, B. A., et al. (2023) · Molecular Cell · doi:10.1016/j.molcel.2022.12.013 · Cited by 51
Linker-free PROTACs efficiently induce the degradation of oncoproteins
Zhang, J., Chen, C., Chen, X., Liao, K., Li, F., Song, X., Liu, C., Su, M.-Y., Sun, H., Hou, T., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-60107-7 · Cited by 51
Structural and Functional Insights into GID/CTLH E3 Ligase Complexes
Maitland, M. E. R., Lajoie, G., Shaw, G. S., & Schild‐Poulter, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23115863 · Cited by 54
Synthetic protein circuits for programmable control of mammalian cell death
Xia, S., Lu, A. C., Tobin, V. R., Luo, K., Moeller, L., Shon, D. J., Du, R., Linton, J. M., Sui, M. Y., Horns, F., et al. (2024) · Cell · doi:10.1016/j.cell.2024.03.031 · Cited by 51
Using continuous directed evolution to improve enzymes for plant applications
García-García, J. D., Gelder, K. V., Joshi, J., Bathe, U., Leong, B. J., Bruner, S. D., Liu, C. C., & Hanson, A. D. (2021) · PLANT PHYSIOLOGY · doi:10.1093/plphys/kiab500 · Cited by 48
Applications of Bacterial Degrons and Degraders — Toward Targeted Protein Degradation in Bacteria
Izert, M. A., Klimecka, M. M., & Górna, M. W. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.669762 · Cited by 50
A C-terminal glutamine recognition mechanism revealed by E3 ligase TRIM7 structures
Liang, X., Xiao, J. H., Li, X., Liu, Y., Lu, Y. P., Wen, Y., Li, Z., Che, X., Ma, Y., Zhang, X., et al. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-01128-x · Cited by 47
Signaling Pathways Regulated by UBR Box-Containing E3 Ligases
Kim, J. G., Shin, H., Seo, T., Nawale, L., Han, G., Kim, B. Y., Kim, S. J., & Cha‐Molstad, H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22158323 · Cited by 48
Biallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications
Chelban, V., Aksnes, H., Maroofian, R., LaMonica, L. C., Seabra, L., Siggervåg, A., Devic, P., Shamseldin, H. E., Vandrovcová, J., Murphy, D. P., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-46354-0 · Cited by 48
New beginnings and new ends: methods for large-scale characterization of protein termini and their use in plant biology
Perrar, A., Dißmeyer, N., & Huesgen, P. F. (2019) · Journal of Experimental Botany · doi:10.1093/jxb/erz104 · Cited by 47
Integration of proteome and transcriptome refines key molecular processes underlying oil production in Nannochloropsis oceanica
You, W., Wei, L., Gong, Y., Hajjami, M. E., Xu, J., & Poetsch, A. (2020) · Biotechnology for Biofuels · doi:10.1186/s13068-020-01748-2 · Cited by 45
Targeting methionine aminopeptidase 2 in cancer, obesity, and autoimmunity
Grocin, A. G., Kallemeijn, W. W., & Tate, E. W. (2021) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2021.07.004 · Cited by 45
Targeted Protein Degradation to Overcome Resistance in Cancer Therapies: PROTAC and N-Degron Pathway
Kim, H., Park, J., & Kim, J. (2022) · Biomedicines · doi:10.3390/biomedicines10092100 · Cited by 45
Folding of heterologous proteins in bacterial cell factories: Cellular mechanisms and engineering strategies
Rong, Y., Jensen, S. I., Lindorff‐Larsen, K., & Nielsen, A. T. (2022) · Biotechnology Advances · doi:10.1016/j.biotechadv.2022.108079 · Cited by 47
The lowdown on breakdown: Open questions in plant proteolysis
Eckardt, N. A., Avin‐Wittenberg, T., Bassham, D. C., Chen, P., Chen, Q., Fang, J., Genschik, P., Ghifari, A. S., Guercio, A. M., Gibbs, D. J., et al. (2024) · The Plant Cell · doi:10.1093/plcell/koae193 · Cited by 47
Hijacking Methyl Reader Proteins for Nuclear-Specific Protein Degradation
Nalawansha, D. A., Li, K., Hines, J. F., & Crews, C. M. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c00874 · Cited by 44
Evolution-Driven Versatility of N Terminal Acetylation in Photoautotrophs
Giglione, C., & Meinnel, T. (2020) · Trends in Plant Science · doi:10.1016/j.tplants.2020.11.012 · Cited by 43
A critical discussion on the relationship between E3 ubiquitin ligases, protein degradation, and skeletal muscle wasting: it’s not that simple
Hughes, D. C., Goodman, C. A., Baehr, L. M., Gregorevic, P., & Bodine, S. C. (2023) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00457.2023 · Cited by 42
Molecular recognition of peptides and proteins by cucurbit[ n ]urils: systems and applications
Armstrong, L., Chang, S. L., Clements, N., Hirani, Z., Kimberly, L. B., Odoi-Adams, K., Suating, P., Taylor, H. F., Trauth, S. A., & Urbach, A. R. (2024) · Chemical Society Reviews · doi:10.1039/d4cs00569d · Cited by 43
Targeting plant cysteine oxidase activity for improved submergence tolerance
Taylor‐Kearney, L. J., & Flashman, E. (2021) · The Plant Journal · doi:10.1111/tpj.15605 · Cited by 41
Molecular basis for recognition of Gly/N-degrons by CRL2ZYG11B and CRL2ZER1
Yan, X., Li, Y., Wang, G., Zhou, Z., Song, G., Feng, Q., Zhao, Y., Mi, W., Ma, Z., & Cheng, D. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.06.010 · Cited by 41
Biodegradation of the pyridinecarboxamide insecticide flonicamid by Microvirga flocculans and characterization of two novel amidases involved
Zhao, Y., Guo, L., Wang, L., Jiang, N., Chen, K., & Dai, Y.-J. (2021) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2021.112384 · Cited by 40
Aminopeptidases trim Xaa-Pro proteins, initiating their degradation by the Pro/N-degron pathway
Chen, S., Kim, L., Song, H. K., & Varshavsky, A. J. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2115430118 · Cited by 42
Self-citation
Non-canonical substrate recognition by the human WDR26-CTLH E3 ligase regulates prodrug metabolism
Gottemukkala, K. V., Chrustowicz, J., Sherpa, D., Sepic, S., Vu, D. T., Karayel, Ö., Papadopoulou, E. C., Groß, A., Schorpp, K., von Gronau, S., et al. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.04.014 · Cited by 39
A chemical probe to modulate human GID4 Pro/N-degron interactions
Owens, D. D. G., Maitland, M. E. R., Yazdi, A. K., Song, X., Reber, V., Schwalm, M. P., Machado, R. A. C., Bauer, N., Wang, X., Szewczyk, M. M., et al. (2024) · Nature Chemical Biology · doi:10.1038/s41589-024-01618-0 · Cited by 39
Targeted Protein Degradation Technology and Nanomedicine: Powerful Allies against Cancer
Lin, J., Liu, H., Wu, Y., Jin, J., Zhou, Y., Zhang, H., Nagle, D. G., Chen, H., Zhang, W., & Luan, X. (2023) · Small · doi:10.1002/smll.202207778 · Cited by 38
Multifaceted N-Degron Recognition and Ubiquitylation by GID/CTLH E3 Ligases
Chrustowicz, J., Sherpa, D., Teyra, J., Loke, M. S., Popowicz, G. M., Basquin, J., Sattler, M., Prabu, J. R., Sidhu, S. S., & Schulman, B. A. (2021) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.167347 · Cited by 38
N-degron-mediated degradation and regulation of mitochondrial PINK1 kinase
Eldeeb, M. A., & Ragheb, M. A. (2020) · Current Genetics · doi:10.1007/s00294-020-01062-2 · Cited by 36
DEGRONOPEDIA: a web server for proteome-wide inspection of degrons
Szulc, N. A., Stefaniak, F., Piechota, M., Soszyńska, A., Piórkowska, G., Cappannini, A., Bujnicki, J. M., Maniaci, C., & Pokrzywa, W. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae238 · Cited by 35

Authors: Varshavsky, A.
Affiliations: California Institute of Technology (US)
Corresponding author: Varshavsky, Alexander
ORCID: Varshavsky, Alexander
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2019-01-07
Volume: 116
Issue: 2
Pages: 358-366
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.1816596116
PMC: PMC6329975
OpenAlex: W2910161842
Cited by: 544
References: 82
Citations by year: 2026: 52 · 2025: 71 · 2024: 79 · 2023: 84 · 2022: 77 · 2021: 77 · 2020: 68 · 2019: 36
FWCI: 5.66
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.pnas.org/site/aboutpnas/licenses.xhtml (vor, 182 d)
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
CaltechAUTHORS (California Institute of Technology) (submittedVersion)
Funders: HHS | National Institutes of Health (DK039520, GM031530)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Keywords: N-degron, protein degradation, N-end rule, protein destabilization, polyubiquitination, proteolytic pathways, short-lived proteins, protein quality control
MeSH terms: Protein Domains, Amino Acid Sequence, Animals, Humans, Amino Acid Motifs, Proteolysis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

N-degron and C-degron pathways of protein degradation

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks