A mechanism of ubiquitin-independent proteasomal degradation of the tumor suppressors p53 and p73
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Protein degradation is an essential and highly regulated process. The proteasomal degradation of the tumor suppressors p53 and p73 is regulated by both polyubiquitination and by an ubiquitin-independent process. Here, we show that this ubiquitin-independent process is mediated by the 20S proteasomes and is regulated by NQO1. NQO1 physically interacts with p53 and p73 in an NADH-dependent manner and protects them from 20S proteasomal degradation. Remarkably, the vast majority of NQO1 in cells is found in physical association with the 20S proteasomes, suggesting that NQO1 functions as a gatekeeper of the 20S proteasomes. We further show that this pathway plays a role in p53 accumulation in response to ionizing radiation. Our findings provide the first evidence for in vivo degradation of p53 and p73 by the 20S proteasomes and its regulation by NQO1 and NADH level.
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NADH binds and stabilizes 26S proteasomes and may also regulate 20S proteasomes.
“Interestingly, the reduced form of NAD+, NADH, binds and stabilizes 26S proteasomes, and may also regulate the function of 20S proteasomes, the two main proteolytic complexes (Asher et al., 2005; Tsvetkov et al., 2014).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Asher et al., 2005
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“…Wojciak et al., 2009; Lee et al., 2010), various PTMs (Kostic et al., 2006; Grimmler et al., 2007; Zhan et al., 2007; Galea et al., 2008b; Mitrea et al., 2014), and regulated degradation (Asher et al., 2005; Tsvetkov et al., 2008, 2009b, 2012; Suskiewicz et al., 2011; Wiggins et al., 2011).”
BackgroundHu, G., Wu, Z., Uversky, V. N., & Kurgan, L. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18122761 · Cited by 105 · see citing works
Mechanisms and regulation of substrate degradation by the 26S proteasome
Arkinson, C., Dong, K. C., Gee, C. L., & Martin, A. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00778-0 · Cited by 112 · see citing works
Tsvetkov, P., Asher, G., Paz, A., Reuven, N. B., Sussman, J. L., Silman, I., & Shaul, Y. (2007) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.21614 · Cited by 105 · see citing works
Self-citationUbiquitin-independent proteasomal degradation driven by C-degron pathways
Makaros, Y., Raiff, A., Timms, R. T., Wagh, A. R., Israel-Gueta, M., Bekturova, A., Guez-Haddad, J., Brodsky, S., Opatowsky, Y., Glickman, M. H., et al. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.04.023 · Cited by 101 · see citing works
Context‐dependent resistance to proteolysis of intrinsically disordered proteins
Suskiewicz, M. J., Sussman, J. L., Silman, I., & Shaul, Y. (2011) · Protein Science · doi:10.1002/pro.657 · Cited by 100 · see citing works
“Many IDPs have been shown to undergo degradation by 20S CP both in vivo and in vitro, including a-synuclein,(50) c-Jun,(51) eIF4F and eIF3,(52) HIF-1a,(53) p16 and p21,(54) Rb,(55) p53, and p73.(56) Indeed, we have suggested that susceptibility to Ub-independent proteolysis by 20S CP is a general property of IDPs.”
BackgroundSelf-citationAzoreductases in drug metabolism
Ryan, A. J. (2016) · British Journal of Pharmacology · doi:10.1111/bph.13571 · Cited by 99 · see citing works
“…(Yang et al., 2014) and pancreatic tumours (Lewis et al., 2005). hNQO1 is known to control the degradation of a range of proteins by the proteasome including the tumour suppressors p53 (Asher et al., 2001) and p73 (Asher et al., 2005), which is likely to contribute to its role in tumourigenesis.”
BackgroundNolan, K. A., Doncaster, J. R., Dunstan, M. S., Scott, K. A., Frenkel, A. D., Siegel, D. M., Ross, D., Barnes, J. H., Levy, C., Leys, D., et al. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm9011609 · Cited by 99 · see citing works
Beaver, S. K., Mesa‐Torres, N., Pey, A. L., & Timson, D. J. (2019) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2019.05.002 · Cited by 96 · see citing works
“P187S also affects the intracellular stability of p53 and p73 as interactors of NQO1 [152, 163, 164], although whether this reflects structural alterations, protein:protein interactions (PPI) or just mirrors the low intracellular stability of the polymorphism has been controversial.”
BackgroundProcessing of autophagic protein LC3 by the 20S proteasome
Gao, Z., Gammoh, N., Wong, P., Erdjument‐Bromage, H., Tempst, P., & Jiang, X. (2010) · Autophagy · doi:10.4161/auto.6.1.10928 · Cited by 96 · see citing works
“However, this model has been recently challenged by the observations that in addition to unstructured polypeptide substrates, several well-folded proteins can also serve as the substrates for the 20S proteasome in an ATP- and ubiquitin-independent manner.(4-8,10) In this study, we demonstrate in vitro that the autopha…”
BackgroundInfluentialGlickman, M. H., & Raveh, D. (2005) · FEBS Letters · doi:10.1016/j.febslet.2005.04.048 · Cited by 96 · see citing works
“, ODC, p53, c-jun, p73, and Rpn4 itself can be degraded – at least occasionally – by the 20S CP in an E3-independent manner [48,49], most substrates of the 26S proteasome are covalently modified with ubiquitin chains by a cascade of E1”
BackgroundThe Protein Level of PGC-1α, a Key Metabolic Regulator, Is Controlled by NADH-NQO1
Adamovich, Y., Shlomai, A., Tsvetkov, P., Umansky, K. B., Reuven, N. B., Estall, J. L., Spiegelman, B. M., & Shaul, Y. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01672-12 · Cited by 95 · see citing works
“The p73 isoform known not to bind NQO1 (39) served as a negative control.”
BackgroundInfluentialSelf-citationLiu, F., Yu, G., Wang, G., Liu, H., Wu, X., Wang, Q., Liu, M., Liao, K., Wu, M., Cheng, X., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042138 · Cited by 91 · see citing works
“. Such a differentiated expression mode of NQO1 between tumors and normal tissues suggests that NQO1 target drugs would be highly selective in killing tumor cells while saving normal tissues. RH1 is a drug candidate bioactivated by NQO1 to produce hydroquinone in the activation of the aziridine rings and subsequent DN…”
BackgroundThe proteasome and its role in the nervous system
Türker, F., Cook, E. K., & Margolis, S. S. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.04.003 · Cited by 92 · see citing works
PA28αβ: The Enigmatic Magic Ring of the Proteasome?
Cascio, P. (2014) · Biomolecules · doi:10.3390/biom4020566 · Cited by 91 · see citing works
“Furthermore, several recent reports indicate that some loosely-folded, short-lived regulatory, viral and oxidized proteins are degraded in vivo by the 20S proteasome in an ATP- and ubiquitin-independent manner [126–133].”
BackgroundGankyrin: a new oncoprotein and regulator of pRb and p53
Dawson, S. P., Higashitsuji, H., Wilkinson, A. J., Fujita, J., & Mayer, R. J. (2006) · Trends in Cell Biology · doi:10.1016/j.tcb.2006.03.001 · Cited by 88 · see citing works
Functional Differences between Proteasome Subtypes
Habib, J. A., Lesenfants, J., Vigneron, N., & den Eynde, B. J. V. (2022) · Cells · doi:10.3390/cells11030421 · Cited by 88 · see citing works
Yes-Associated Protein (YAP) is a critical mediator of c-Jun-dependent apoptosis
Danovi, S. A., Rossi, M., Gudmundsdottir, K. K., Yuan, M., Melino, G., & Basu, S. (2007) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402226 · Cited by 86 · see citing works
Effects of Histone Deacetylase Inhibitors on HIF-1
Liang, D., Kong, X., & Sang, N. (2006) · Cell Cycle · doi:10.4161/cc.5.21.3409 · Cited by 85 · see citing works
Pey, A. L., Megarity, C. F., & Timson, D. J. (2018) · Bioscience Reports · doi:10.1042/bsr20180459 · Cited by 84 · see citing works
Zhu, H., & Li, Y. (2011) · Cardiovascular Toxicology · doi:10.1007/s12012-011-9136-9 · Cited by 84 · see citing works
“In addition to p53, NQO1 was also found to regulate the ubiquitin-independent 20S proteasomal degradation of p73a and p33, two other tumor suppressors though the in vivo biological significance of such a regulation is currently unknown [ 18 , 19].”
BackgroundGarate, M., Wong, R. P. C., Campos, E. I., Wang, Y., & Li, G. (2008) · EMBO Reports · doi:10.1038/embor.2008.48 · Cited by 82 · see citing works
“It has been shown previously that NQO1 modulates the degradation of proteins such as p53 and p73 (Asher et al, 2005a) or ornitine decarboxylase (Asher et al, 2005b) in the 20S proteasome.”
BackgroundGomes, A. V., Young, G. W., Wang, Y., Zong, C., Eghbali, M., Drews, O., Lu, H., Stefani, E., & Ping, P. (2008) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m800058-mcp200 · Cited by 82 · see citing works
“The 20 S proteasome is important for degrading oxidized proteins and has also been shown to degrade non-oxidized and non-ubiquitinated substrates, such as ornithine decarboxylase, p53 and p73 (5, 6).”
BackgroundDifferential control of TAp73 and ΔNp73 protein stability by the ring finger ubiquitin ligase PIR2
Sayan, B. S., Yang, A. L., Conforti, F., Tucci, P., Piro, M. C., Browne, G. J., Agostini, M., Bernardini, S., Knight, R. A., Mak, T. W., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0911828107 · Cited by 81 · see citing works
“Another mechanism of p73 degradation involves the ubiquitin-independent 20S proteasomal pathway, regulated by NAD(P)H quinone oxidoreductase 1 together with NADH (26).”
BackgroundMechanism of Cell Cycle Regulation by FIP200 in Human Breast Cancer Cells
Melkoumian, Z. K., Xu, P., Gan, B., Wu, X., & Guan, J. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-4142 · Cited by 77 · see citing works
“NQO1 has been shown to stabilize p53 by preventing its degradation by 20S proteasomes via ubiquitin and Mdm2-independent mechanism (35).”
Uversky, V. N. (2017) · Autophagy · doi:10.1080/15548627.2017.1384889 · Cited by 76 · see citing works
Ubiquitin and Ubiquitin-Like Modifications of the p53 Family
Watson, I. R., & Irwin, M. S. (2006) · Neoplasia · doi:10.1593/neo.06439 · Cited by 76 · see citing works
“Studies have demonstrated that dicumarol and other inhibitors of NQO1 induce the degradation of p53, and the majority of NQO1 associates with 20S proteasomes [104–106].”
NQO1 and NQO2 Regulation of Humoral Immunity and Autoimmunity
Iskander, K. S., Li, J. L., Han, S., Zheng, B. Q., & Jaiswal, A. K. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m605809200 · Cited by 76 · see citing works
Antizyme1 mediates AURKAIP1-dependent degradation of Aurora-A
Lim, S. K., & Gopalan, G. (2007) · Oncogene · doi:10.1038/sj.onc.1210482 · Cited by 74 · see citing works
“…we have on the significance and the physiological relevance of this alternative pathway, the growing list of protein substrates (Jin et al., 2003; Asher et al., 2005; Sdek et al., 2005) targeted to the proteasome in the absence of ubiquitination suggests that the Ub-independent route to the…”
BackgroundVoutsadakis, I. A. (2007) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2007.00032.x · Cited by 74 · see citing works
Tabakin-Fix, Y., Azran, I., Schavinsky‐Khrapunsky, Y., Levy, O., & Aboud, M. (2005) · Carcinogenesis · doi:10.1093/carcin/bgi274 · Cited by 72 · see citing works
Effective Gamification of the Stop-Signal Task: Two Controlled Laboratory Experiments
Friehs, M. A., Dechant, M., Vedress, S., Frings, C., & Mandryk, R. L. (2020) · JMIR Serious Games · doi:10.2196/17810 · Cited by 72 · see citing works
Wiggins, C. M., Tsvetkov, P., Johnson, M., Joyce, C. L., Lamb, C. A., Bryant, N. J., Komander, D., Shaul, Y., & Cook, S. J. (2011) · Journal of Cell Science · doi:10.1242/jcs.058438 · Cited by 70 · see citing works
“Similarly, ornithine decarboxylase (Asher et al., 2005b), p21CIP1 (Touitou et al., 2001) and IBa (Krappmann et al., 1996; Alvarez-Castelao and Castaño, 2005) are all poly-Ub but can also be degraded by 20S.”
BackgroundMethodSelf-citationStructure and apoptotic function of p73
Yoon, M.-K., Ha, J., Lee, M.-S., & Chi, S. (2015) · BMB Reports · doi:10.5483/bmbrep.2015.48.2.255 · Cited by 69 · see citing works
“the TAp73 and DNp73 isoforms are degraded by either calpains (6) or in an ubiquitin-dependent or -independent manner (7, 8), which keeps their steady-state levels low.”
BackgroundMethodCraxton, A., Butterworth, M., Harper, N. W., Fairall, L., Schwabe, J. W. R., Ciechanover, A. J., & Cohen, G. M. (2012) · Cell Death and Differentiation · doi:10.1038/cdd.2012.16 · Cited by 67 · see citing works
“In more general terms, there is an expanding list of unstructured proteins including p53, p73a, p21 IkB, MCL-1 and BIM that are proposed 20S proteasome substrates based on in vitro studies.(12,14,15,22) Our studies with NOXA suggest that some of these proteins may be bona fide 26S proteasome substrates in vivo.”
BackgroundRegulation of the p73 protein stability and degradation
Oberst, A., Rossi, M., Salomoni, P., Pandolfi, P. P., Oren, M., Melino, G., & Bernassola, F. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.03.158 · Cited by 66 · see citing works
Suzuki, R., Moriishi, K., Fukuda, K., Shirakura, M., Ishii, K., Shoji, I., Wakita, T., Miyamura, T., Matsuura, Y., & Suzuki, T. (2008) · Journal of Virology · doi:10.1128/jvi.01690-08 · Cited by 65 · see citing works
“Accumulating evidence suggests the existence of proteasome-dependent but Ub-independent pathways for protein degradation, and several important molecules, such as p53, p73, Rb, SRC-3, and the hepatitis B virus X protein, have two distinct degradation pathways that function in a Ub-dependent and Ub-independent manner (…”
BackgroundProteostatic regulation in neuronal compartments
Giandomenico, S. L., Alvarez‐Castelao, B., & Schuman, E. M. (2021) · Trends in Neurosciences · doi:10.1016/j.tins.2021.08.002 · Cited by 61 · see citing works
“Adding complexity to the system, it is important to note that some times the same protein can be degraded in both a ubiquitin-dependent and -independent manner [89], and that several proteins are degraded by the proteasome in a ubiquitin-independent manner [90] with the aid of factors such as NQO1 or DJ-1 [91,92].”
BackgroundPey, A. L., Megarity, C. F., & Timson, D. J. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.08.011 · Cited by 62 · see citing works
Tsvetkov, P., Adamovich, Y., Elliott, E., & Shaul, Y. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.193276 · Cited by 64 · see citing works
Self-citationLienhart, W., Gudipati, V., Uhl, M. K., Binter, A., Pulido, S., Saf, R., Zangger, K., Gruber, K. F., & Macheroux, P. (2014) · FEBS Journal · doi:10.1111/febs.12975 · Cited by 64 · see citing works
“The structure was solved by molecular replacement with PHASER [25], and the detwinned dataset was produced with DETWIN [3].”
Methodp73 Alternative Splicing: Exploring a Biological Role for the C-Terminal Isoforms
Вихрева, П. Н., Melino, G., & Amelio, I. (2018) · Journal of Molecular Biology · doi:10.1016/j.jmb.2018.04.034 · Cited by 63 · see citing works
“The C-terminal SAM domain region of p73α is also required for direct binding to NAD(P)H quinone oxidoreductase 1 (NQO1), which leads to it ubiquitin-independent proteasomal degradation [52].”
BackgroundA hydride transfer complex reprograms NAD metabolism and bypasses senescence
Igelmann, S., Lessard, F., Uchenunu, O., Bouchard, J., Fernandez-Ruiz, A., Rowell, M.-C., Lopes-Paciencia, S., Papadopoli, D., Fouillen, A., Ponce, K. J., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.08.028 · Cited by 60 · see citing works
Opoku-Nsiah, K., & Gestwicki, J. E. (2018) · Translational research · doi:10.1016/j.trsl.2018.05.002 · Cited by 61 · see citing works
“The UPS and UIPS have both been shown to facilitate the rapid proteasomal degradation of IDPs, such as p53 and p73.(25)”
Roles of NAD(P)H:quinone Oxidoreductase 1 in Diverse Diseases
Lee, W. S., Ham, W., & Kim, J. (2021) · Life · doi:10.3390/life11121301 · Cited by 61 · see citing works
“In addition to p53, NQO1 has also been shown to regulate the ubiquitin-independent 20S proteasomal degradation of p33 and p73α—two other tumor suppressors [1,89,90].”
Background
- Authors
- Asher, G., Tsvetkov, P., Kahana, C., & Shaul, Y.
- Affiliations
- Weizmann Institute of Science (IL)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2005-02-01
- Volume
- 19
- Issue
- 3
- Pages
- 316-321
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC546509
- OpenAlex
- W2099952208
- Cited by
- 367
- References
- 24
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 8 · 2023: 8 · 2022: 14 · 2021: 23 · 2020: 17 · 2019: 21 · 2018: 16 · 2017: 26 · 2016: 15 · 2015: 13 · 2014: 23 · 2013: 11 · 2012: 18
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Israel Academy of Sciences and Humanities
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- p53, p73, 20S proteasome, NQO1, NADH, tumor suppressor degradation, ionizing radiation response, protein degradation regulation
- MeSH terms
- Tumor Protein p73, Animals, Coenzymes, DNA-Binding Proteins, Humans, Nuclear Proteins, Protein Binding, Genes, Tumor Suppressor, Tumor Suppressor Protein p53, NAD(P)H Dehydrogenase (Quinone), Tumor Suppressor Proteins, Ubiquitin, Protein Interaction Mapping, Proteasome Endopeptidase Complex
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