SIRT5 Desuccinylates and Activates Pyruvate Kinase M2 to Block Macrophage IL-1β Production and to Prevent DSS-Induced Colitis in Mice
Open accessAbstract
LPS-activated macrophages undergo a metabolic shift from dependence on mitochondria-produced ATP to reliance on aerobic glycolysis, where PKM2 is a critical determinant. Here, we show that PKM2 is a physiological substrate of SIRT5 and that SIRT5-regulated hypersuccinylation inhibits the pyruvate kinase activity of PKM2 by promoting its tetramer-to-dimer transition. Moreover, a succinylation-mimetic PKM2 K311E mutation promotes nuclear accumulation and increases protein kinase activity. Furthermore, we show that SIRT5-dependent succinylation promotes PKM2 entry into nucleus, where a complex of PKM2-HIF1α is formed at the promoter of IL-1β gene in LPS-stimulated macrophages. Activation of PKM2 using TEPP-46 attenuates Sirt5-deficiency-mediated IL-1β upregulation in LPS-stimulated macrophages. Finally, we find that Sirt5-deficient mice are more susceptible to DSS-induced colitis, which is associated with Sirt5 deficiency prompted PKM2 hypersuccinylation and boosted IL-1β production. In conclusion, our findings reveal a mechanism by which SIRT5 suppresses the pro-inflammatory response in macrophages at least in part by regulating PKM2 succinylation, activity, and function.
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ACL is required for response to growth factor stimulation and during differentiation, including differentiation of murine 3T3-L1 pre-adipocytes into adipocytes.
“One of the earliest studies to identify a role for ACL in histone acetylation demonstrated a requirement for this gene in response to growth factor stimulation and during differentiation, for example the differentiation of murine 3T3- L1 pre-adipocytes into adipocytes.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [54]
Histone acetylation in mammalian cells is dependent on ACL, and ACL silencing decreases histone acetylation.
“It has been demonstrated in mammalian cells that histone acetylation is dependent on ACL, the enzyme that converts citrate into acetyl-CoA, a required co-factor for acetylation,54 with ACL silencing decreasing the degree of histone acetylation.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [54]
During adipocyte differentiation, global histone acetylation is determined by glucose availability through an ACL-dependent pathway.
“It was shown that during adipocyte differentiation, global histone acetylation is determined by glucose availability through an ACL-dependent pathway 54.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [54]
Cells depleted of ACL contain less lipid than control cells.
“Cells depleted of ACL contained visibly less lipid than control cells.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [54]
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References 45 · Cited by 340
- Authors
- Wang, F., Wang, K., Xu, W., Zhao, S., Ye, D., Wang, Y., Xu, Y., Zhou, L., Chu, Y., Zhang, C., Qin, X., Yang, P., & Yu, H.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- Fudan University (CN)
- First Affiliated Hospital of GuangXi Medical University (CN)
- Corresponding author
- Yang, Pengyuan
- Yu, Hongxiu
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-06
- Volume
- 19
- Issue
- 11
- Pages
- 2331-2344
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2626828299
- Cited by
- 340
- References
- 45
- Citations by year
- 2026: 35 · 2025: 51 · 2024: 42 · 2023: 40 · 2022: 55 · 2021: 39 · 2020: 34 · 2019: 21 · 2018: 17 · 2017: 3 · 2015: 1
- FWCI
- 12.56
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Key Basic Research Program of China (2013CB910502, 2013CB910500)
- Natural Science Foundation of China (81672746, 81472566, 81201534)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- SIRT5, PKM2, succinylation, macrophages, IL-1β, DSS-induced colitis, lipopolysaccharide stimulation, aerobic glycolysis, HIF-1α, nuclear translocation, TEPP-46, inflammation, gut microbiota
- MeSH terms
- Animals, Colitis, Humans, Macrophages, Male, Phosphorylation, Pyruvate Kinase, Transfection, Signal Transduction, Mice, Knockout, Sirtuins, Mice, Interleukin-1beta
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