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Lysine Glutarylation Is a Protein Posttranslational Modification Regulated by SIRT5
Open accessAbstract
We report the identification and characterization of a five-carbon protein posttranslational modification (PTM) called lysine glutarylation (Kglu). This protein modification was detected by immunoblot and mass spectrometry (MS), and then comprehensively validated by chemical and biochemical methods. We demonstrated that the previously annotated deacetylase, sirtuin 5 (SIRT5), is a lysine deglutarylase. Proteome-wide analysis identified 683 Kglu sites in 191 proteins and showed that Kglu is highly enriched on metabolic enzymes and mitochondrial proteins. We validated carbamoyl phosphate synthase 1 (CPS1), the rate-limiting enzyme in urea cycle, as a glutarylated protein and demonstrated that CPS1 is targeted by SIRT5 for deglutarylation. We further showed that glutarylation suppresses CPS1 enzymatic activity in cell lines, mice, and a model of glutaric acidemia type I disease, the last of which has elevated glutaric acid and glutaryl-CoA. This study expands the landscape of lysine acyl modifications and increases our understanding of the deacylase SIRT5.
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“This work resulted in the identification of novel modifications targeted by SIRT5: succinylation, malonylation and glutarylation as described in details below ((Du et al. 2011{Zhang, 2011 #16);(Peng et al. 2011);(Tan et al. 2014)}.”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Tan et al. 2014
In the citing paper
“SIRT5 positively regulates CPS1 activity by mediating desuccinylation, deglutarylation and possibly by deacetylation across multiple sites ((Du et al. 2011))((Tan et al. 2014))((Nakagawa et al. 2009)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Tan et al. 2014
In the citing paper
“Mice lacking SIRT5 fail to upregulate CPS1 activity and show elevated blood ammonia under these conditions ((Nakagawa et al. 2009))((Tan et al. 2014)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Tan et al. 2014
In the citing paper
“Moreover, HMGCS2 is also subject to glutarylation and malonylation ((Tan et al. 2014))((Nishida et al. 2015)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Tan et al. 2014
In the citing paper
“Interestingly, lysine 88 is also a target of succinylation and glutarylation ((Rardin, He, et al. 2013))((Tan et al. 2014)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Tan et al. 2014
In the citing paper
“Both MnSOD and the various mitochondrial superoxide sources are acylated ((Rardin, Newman, et al. 2013), (Rardin, He, et al. 2013);(Tan et al. 2014)); MnSOD also carries glutarylation, succinylation, and acetylation at functionally required lysine residues near its active site, K122 in particular bears all three modifications ((Tao et al. 2010)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Tan et al. 2014
In the citing paper
“Mass-spectrometry data has shown that there are an abundance of histone crotonylation sites in all four core histones22,40.”
From Histone deacetylase (HDAC) 1 and 2 complexes regulate both histone acetylation and crotonylation in vivo (2018) · cites this paper as [40]
In the citing paper
“For example, SIRT5 exhibits efficient activity to lysine desuccinylation, demalonylation and glutarylation12-14”
From HDAC8 catalyzes the hydrolysis of long chain fatty acyl lysine (2016) · cites this paper as [14]
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Citations
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SIRT5-mediated GLS and GDH desuccinylation attenuates autophagy in MAC-T cells induced by ammoniaPreprint
Yang, H., Gao, S., Lu, G., He, J., Dong, J., Zhang, X., Liu, L., Zhong, K., Zha, G., Han, L., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.08.26.609685
Questel, E. L., Besnard, C., Atger, F., Foucher, Y., Tollec, A., Pakulska, V., Oliveira, A. R., Cloteau, C., Gourdel, M., Nemazanyy, I., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.03.607283
“…the differentially impacted malonylated lysine by ACSF3 KD, most if not all can also be modified by multiple other type of PTMs such as ubiquitination or other acylations like acetylation, glutarylation or succinylation with potential consequences on their stability or functionality 24,26,58,59 .”
BackgroundZhu, Z.-Y., Mao, P.-Z., Tarn, C., & Cao, Y. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.07.03.662920
Li, S., Shen, S., Hong, Y., Ding, K., Chen, S., Chen, J., Wang, C., Wen, Y., Mo, G., Yu, L., et al. (2026) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-026-06308-9 · Cited by 3
“HL-1 cells were seeded at 1 × 10⁶ cells per well in 96-well plates, treated as indicated, washed with cold PBS and lysed in 100 µL ice-cold Assay Buffer 23.”
InfluentialA protocol for detection of mitochondrial protein malonylation and succinylation
Zhao, J., Cao, X., Wang, J., Xu, S., Hu, H., Pei, X., Wei, T., & Xiao, M. (2025) · Biophysics Reports · doi:10.52601/bpr.2025.250047
Lysine- R 2HGylation identified as a post-translational modification in R 2HG-elevated cancersPreprint
Zhao, Q., Huang, P., Yuan, C., Xia, P., Gu, Q., Yang, T., Li, X., Tian, R., & Yang, D. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.03.680013
“In small lysine acylations, antibody-assisted enrichment has helped the discovery and study of many PTMs, including malonylation 44 , succinylation 41 , glutarylation 45 , and lactylation 46 .”
Richert, A. C., Zhang, Y., Bharathi, S. S., Hernandez, A., Dodatko, T., Bons, J., Roundtree, K. E., Stauffer, B. B., Yu, C., Schilling, B., et al. (2025) · The FASEB Journal · doi:10.1096/fj.202502381r
“Among acyl-CoA metabolites, the di-carboxylic species DC 4 - CoA (succinyl-CoA) and DC 5 - CoA are known to exhibit high chemical reactivity toward the lysine residues of proteins [51, 52].”
Self-citationYang, Y., Yu, Z., Gao, R., Zhang, Y., Zhang, Z., Zhong, X., Jiao, L., Du, K., Wu, Y., Wei, M., et al. (2025) · Journal of Advanced Research · doi:10.1016/j.jare.2025.11.050 · Cited by 1
Self-citationDifferential regulation of SIRT5 activity by reduced nicotinic acid riboside (NARH)
Hamza, A., Donu, D., Boyle, E., Madhusudhana, R., Curry, A. M., & Cen, Y. (2025) · RSC Chemical Biology · doi:10.1039/d5cb00191a
Lacombe, M., Lamarche, F., Wever, O. D., Padilla‐Benavides, T., Carlson, A., Khan, I., Huna, A., Vacher, S., Calmel, C., Desbourdes, C., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16851102
Lacombe, M., Lamarche, F., Wever, O. D., Padilla‐Benavides, T., Carlson, A., Khan, I., Huna, A., Vacher, S., Calmel, C., Desbourdes, C., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16851153
Lacombe, M., Lamarche, F., Wever, O. D., Padilla‐Benavides, T., Carlson, A., Khan, I., Huna, A., Vacher, S., Calmel, C., Desbourdes, C., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16851156
Lacombe, M., Lamarche, F., Wever, O. D., Padilla‐Benavides, T., Carlson, A., Khan, I., Huna, A., Vacher, S., Calmel, C., Desbourdes, C., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16851078
Lacombe, M., Lamarche, F., Wever, O. D., Padilla‐Benavides, T., Carlson, A., Khan, I., Huna, A., Vacher, S., Calmel, C., Desbourdes, C., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16851132
Xue, C., Qiao, Z., Chen, X., Cao, P., Liu, K., Liu, S., Lu, Y., & Gong, Z. (2020) · Figshare · doi:10.6084/m9.figshare.12544340
Zhang, L., Wang, H., Xue, C., Liu, Y., Zhang, Y., Liu, Z., Meng, X., Liu, M., & Zhao, J. (2024) · Figshare · doi:10.6084/m9.figshare.26721000
Self-citationZhang, L., Wang, H., Xue, C., Liu, Y., Zhang, Y., Liu, Z., Meng, X., Liu, M., & Zhao, J. (2024) · Figshare · doi:10.6084/m9.figshare.26721024
Self-citationLacombe, M., Lamarche, F., Wever, O. D., Padilla‐Benavides, T., Carlson, A., Khan, I., Huna, A., Vacher, S., Calmel, C., Desbourdes, C., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16851108
Zhang, L., Wang, H., Xue, C., Liu, Y., Zhang, Y., Liu, Z., Meng, X., Liu, M., & Zhao, J. (2024) · Figshare · doi:10.6084/m9.figshare.26720985
Self-citationZhang, L., Wang, H., Xue, C., Liu, Y., Zhang, Y., Liu, Z., Meng, X., Liu, M., & Zhao, J. (2024) · Figshare · doi:10.6084/m9.figshare.26721021
Self-citationZhang, L., Wang, H., Xue, C., Liu, Y., Zhang, Y., Liu, Z., Meng, X., Liu, M., & Zhao, J. (2024) · Figshare · doi:10.6084/m9.figshare.26720991
Self-citationLacombe, M., Lamarche, F., Wever, O. D., Padilla‐Benavides, T., Carlson, A., Khan, I., Huna, A., Vacher, S., Calmel, C., Desbourdes, C., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16851093
Zhang, L., Wang, H., Xue, C., Liu, Y., Zhang, Y., Liu, Z., Meng, X., Liu, M., & Zhao, J. (2024) · Figshare · doi:10.6084/m9.figshare.26720994
Self-citationLacombe, M., Lamarche, F., Wever, O. D., Padilla‐Benavides, T., Carlson, A., Khan, I., Huna, A., Vacher, S., Calmel, C., Desbourdes, C., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16851063
Lacombe, M., Lamarche, F., Wever, O. D., Padilla‐Benavides, T., Carlson, A., Khan, I., Huna, A., Vacher, S., Calmel, C., Desbourdes, C., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16851150
Metadata
- Authors
- Tan, M., Peng, C., Anderson, K. A., Chhoy, P., Xie, Z., Dai, L., Park, J., Chen, Y., Huang, H., Zhang, Y., Ro, J., Wagner, G. R., Green, M. F., Madsen, A. S., Schmiesing, J., Peterson, B. S., Xu, G., Ilkayeva, O. R., Muehlbauer, M. J., Braulke, T., Mühlhausen, C., Backos, D. S., Olsen, C. A., McGuire, P. J., Pletcher, S. D., Lombard, D. B., Hirschey, M. D., & Zhao, Y.
- Affiliations
- Chinese Academy of Sciences (CN)
- University of Chicago (US)
- Duke University (US)
- University of Michigan (US)
- Technical University of Denmark (DK)
- University Medical Center Hamburg-Eppendorf (DE)
- University of Colorado Anschutz (US)
- National Institutes of Health (US)
- Corresponding author
- Hirschey, Matthew D.
- Zhao, Yingming
- ORCID
- Tan, Minjia
- Peng, Chao
- Chhoy, Peter
- Xie, Zhongyu
- Dai, Lunzhi
- Huang, He
- Zhang, Yi
- Ro, Jennifer
- Green, Michelle F.
- Madsen, Andreas S.
- Xu, Guofeng
- Ilkayeva, Olga R.
- Muehlbauer, Michael J.
- Braulke, Thomas
- Mühlhausen, Chris
- Backos, Donald S.
- Olsen, Christian A.
- McGuire, Peter J.
- Pletcher, Scott D.
- Lombard, David B.
- Hirschey, Matthew D.
- Zhao, Yingming
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 19
- Issue
- 4
- Pages
- 605-617
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4108075
- OpenAlex
- W2088511656
- Cited by
- 844
- References
- 45
- Citations by year
- 2026: 49 · 2025: 63 · 2024: 86 · 2023: 50 · 2022: 79 · 2021: 106 · 2020: 67 · 2019: 74 · 2018: 80 · 2017: 53 · 2016: 70 · 2015: 50 · 2014: 16
- FWCI
- 32.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Technical University of Denmark, DTU Orbit (Technical University of Denmark, DTU) (submittedVersion)
- Funders
- Lundbeckfonden (R52-2010-5054)
- National Institutes of Health (UL1TR000430)
- National Institute on Alcohol Abuse and Alcoholism (AA022146, R01AA022146)
- National Institute on Aging (F31AG047696, R01AG045351, AG045351, P30AG013283, T32AG000114)
- National Cancer Institute (R21CA177925, CA160036, CA059365-19, U24CA160036, T32CA059365, CA177925)
- National Institute of General Medical Sciences (GM105933, T32GM007105, GM101171, T32GM007315, R01GM101171, R01GM105933)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK096493, P30DK020572)
- National Center for Research Resources (RR020839, U54RR020839)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- SIRT5, protein posttranslational modification, urea cycle, glutaric aciduria type I, glutaryl-CoA, mitochondrial proteins, metabolic enzymes
- MeSH terms
- Acyl Coenzyme A, Animals, Carbamoyl-Phosphate Synthase (Ammonia), Lysine, Models, Biological, Protein Processing, Post-Translational, Mass Spectrometry, Immunoblotting, Molecular Structure, Sirtuins, Proteomics, Mice
About these checks
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