BACE1 SUMOylation increases its stability and escalates the protease activity in Alzheimer’s disease
Open accessAbstract
Amyloid beta (Aβ) is a major pathological marker in Alzheimer's disease (AD), which is principally regulated by the rate-limiting β-secretase (i.e., BACE1) cleavage of amyloid precursor protein (APP). However, how BACE1 activity is posttranslationally regulated remains incompletely understood. Here, we show that BACE1 is predominantly SUMOylated at K501 residue, which escalates its protease activity and stability and subsequently increases Aβ production, leading to cognitive defect seen in the AD mouse model. Compared with a non-SUMOylated K501R mutant, injection of wild-type BACE1 significantly increases Aβ production and triggers cognitive dysfunction. Furthermore, overexpression of wild-type BACE1, but not non-SUMOylated K501R mutant, facilitates senile plaque formation and aggravates the cognitive deficit seen in the APP/PS1 AD mouse model. Together, our data strongly suggest that K501 SUMOylation on BACE1 plays a critical role in mediating its stability and enzymatic activity.
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Sumoylation of BACE1 at residue K501 enhances its stability and Aβ-producing activity.
“it was shown that sumoylation of residue K501 on BACE1 enhances its stability and Aβ-producing activity (31).”
From The β-Secretase BACE1 in Alzheimer’s Disease (2021) · cites this paper as [31]
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BACE1 SUMOylation deregulates phosphorylation and ubiquitination in Alzheimer's disease pathology
Zhao, Y., Zhou, H., Zhao, Y., Liang, Z., Gong, X., Yu, J. H., Huang, T., Yang, C., Wu, M., Xiao, Y., et al. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15870 · Cited by 13 · see citing works
“A previous study shows that SUMOylation of BACE1 at Lys 501 enhances its stability and mediates its intracellular location at endosomes, escalating its protease activity (Bao et al., 2018).”
BackgroundInfluentialBlockage of AEP attenuates TBI-induced tau hyperphosphorylation and cognitive impairments in rats
Liu, Y., Guo, C., Ding, Y., Long, X., Li, W., Ke, D., Wang, Q., Liu, R., Wang, J., Zhang, H., et al. (2020) · Aging · doi:10.18632/aging.103841 · Cited by 12 · see citing works
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Effects of aerobic exercise on hippocampal SUMOylation in APP/PS1 transgenic mice
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The aminosterol Claramine inhibits β-secretase 1–mediated insulin receptor cleavage
Gaborit, B., Govers, R., Altié, A., Brunel, J. M., Morange, P., & Peiretti, F. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100818 · Cited by 9 · see citing works
“There is no consensus regarding the stability of the ubiquitination-deficient BACE1K501R: it was shown to behave like wildtype BACE1 (42) or to be stabilized and accumulate in early and late endosomes/lysosomes (20) or to be destabilized (21).”
BackgroundManna, P. R., Yang, S., Manna, C., Waters, H., Islam, M. A., Reddy, A. P., Rawat, P., & Reddy, P. H. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105969 · Cited by 7 · see citing works
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SUMOylation balance: a key determinant in synapse physiology
Bertozzi, A., Toscanelli, W., Castellitto, G., Grassi, C., & Colussi, C. (2025) · Frontiers in Physiology · doi:10.3389/fphys.2025.1675598 · Cited by 3 · see citing works
HDAC6 regulates BACE1 stability and NLRP3 inflammasome activation in Alzheimer's disease
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UBC-9 Acts in GABA Neurons to Control Neuromuscular Signaling in C. elegans
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Rossi, R., Cano, A. C., Pallarès-Rusiñol, A., Ruiz, A., Martı́, M., & Pividori, M. I. (2025) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2025.118061 · Cited by 2 · see citing works
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Analysis of the BACE1 and Clusterin Genes Expression Levels in Alzheimer’s Disease
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p53 SUMOylation promotes neurogenesis defects in APP/PS1 mice
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SUMOylation in Neural Health and Disease: From Cellular Homeostasis to Neurodegeneration
Oriquat, G., Jasim, I., Gajjar, T. B., Hanumanthayya, M., Ahmad, I. A., Singh, G., Maharana, L., & Bainsal, N. (2026) · DNA and Cell Biology · doi:10.1177/10445498261444640 · Cited by 1 · see citing works
“As a result, A b aggregate levels increase (Bao et al., 2018).”
Sheng, Z., Cao, X., Deng, Y., Zhao, X., & Liang, S. (2023) · Figshare · doi:10.6084/m9.figshare.23819920
Epigenetic Changes in Alzheimer’s Disease and Interventions for Therapy
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The role of SUMOylation in regulating proteins that drive neuronal disease progression
Sidharth, A., & Shin, D. (2026) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2026.102687
“A recent study showed that SUMOylation by SUMO-1 at Lys501 residue in BACE1 enhances its stability and escalates its protease activity [40] (Fig.”
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- Authors
- Bao, J., Qin, M., Mahaman, Y. A. R., Zhang, B., Huang, F., Zeng, K., Xia, Y., Ke, D., Wang, Q., Liu, R., Wang, J.-Z., Ye, K., & Wang, X.
- Affiliations
- Huazhong University of Science and Technology (CN)
- Icahn School of Medicine at Mount Sinai (US)
- Nantong University (CN)
- Emory University (US)
- Corresponding author
- Wang, Xiaochuan
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-03-26
- Volume
- 115
- Issue
- 15
- Pages
- 3954-3959
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5899489
- OpenAlex
- W2789789422
- Cited by
- 50
- References
- 53
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 8 · 2023: 5 · 2022: 3 · 2021: 8 · 2020: 5 · 2019: 5 · 2018: 4
- FWCI
- 3.77
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-10-26)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81571255, 31771114, 31528010)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- BACE1, SUMOylation, Alzheimer's disease, amyloid-beta, beta-secretase, protein stability, proteolytic activity, amyloid precursor protein, amyloid plaques, cognitive impairment, APP/PS1 mice, post-translational regulation
- MeSH terms
- Alzheimer Disease, Animals, Cognition, Disease Models, Animal, Enzyme Stability, Humans, Mice, Transgenic, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amino Acid Motifs, Mice, Amyloid Precursor Protein Secretases, Sumoylation
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