Spermidine induces autophagy by inhibiting the acetyltransferase EP300
Open accessAbstract
Several natural compounds found in health-related food items can inhibit acetyltransferases as they induce autophagy. Here we show that this applies to anacardic acid, curcumin, garcinol and spermidine, all of which reduce the acetylation level of cultured human cells as they induce signs of increased autophagic flux (such as the formation of green fluorescent protein-microtubule-associated protein 1A/1B-light chain 3 (GFP-LC3) puncta and the depletion of sequestosome-1, p62/SQSTM1) coupled to the inhibition of the mammalian target of rapamycin complex 1 (mTORC1). We performed a screen to identify the acetyltransferases whose depletion would activate autophagy and simultaneously inhibit mTORC1. The knockdown of only two acetyltransferases (among 43 candidates) had such effects: EP300 (E1A-binding protein p300), which is a lysine acetyltranferase, and NAA20 (N(α)-acetyltransferase 20, also known as NAT5), which catalyzes the N-terminal acetylation of methionine residues. Subsequent studies validated the capacity of a pharmacological EP300 inhibitor, C646, to induce autophagy in both normal and enucleated cells (cytoplasts), underscoring the capacity of EP300 to repress autophagy by cytoplasmic (non-nuclear) effects. Notably, anacardic acid, curcumin, garcinol and spermidine all inhibited the acetyltransferase activity of recombinant EP300 protein in vitro. Altogether, these results support the idea that EP300 acts as an endogenous repressor of autophagy and that potent autophagy inducers including spermidine de facto act as EP300 inhibitors.
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Spermidine prevents acetylation of autophagy proteins by blocking EP300 acetyltransferase, maintains autophagy flux, preserves mitochondrial function, exhibits anti-inflammatory properties, and prevents stem cell senescence.
“Acetylation of autophagy proteins plays an inhibitory action, and the polyamine spermidine, by blocking the EP300 acetyltransferase, prevents this post-translational modification, maintains autophagy flux, preserves mitochondrial function, exhibits anti-inflammatory properties, and prevents stem cell senescence98.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [98]
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- Authors
- Pietrocola, F., Lachkar, S., Enot, D. P., Niso-Santano, M., Bravo-San Pedro, J. M., Sica, V, Izzo, V, Maiuri, M. C., Madeo, F., Mariño, G., & Kroemer, G.
- Affiliations
- Inserm (FR)
- Institut Gustave Roussy (FR)
- University of Graz (AT)
- Corresponding author
- Mariño, G
- Kroemer, G
- Venue
- Cell Death & Differentiation
- Published
- 2014-12-19
- Volume
- 22
- Issue
- 3
- Pages
- 509-516
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC4326581
- OpenAlex
- W2059107485
- Cited by
- 357
- References
- 39
- Citations by year
- 2026: 52 · 2025: 36 · 2024: 29 · 2023: 32 · 2022: 35 · 2021: 36 · 2020: 35 · 2019: 32 · 2018: 27 · 2017: 17 · 2016: 16 · 2015: 8 · 2014: 1
- FWCI
- 10.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repository University of Extremadura (University of Extremadura) (submittedVersion)
- Funders
- Association pour la Recherche sur le Cancer
- European Commission
- Agence Nationale de la Recherche
- Austrian Science Fund (P 24381, I1000, P 23490)
- Fondation pour la Recherche Médicale
- Ligue Contre le Cancer
- Fondation de France
- Institut National Du Cancer
- Labex Immuno-Oncology
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- spermidine, EP300, autophagy induction, mTORC1, C646, anacardic acid, curcumin, garcinol, p62, LC3
- MeSH terms
- Autophagy, Humans, Spermidine, Cell Line, Tumor, E1A-Associated p300 Protein
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