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PP2A Regulates HDAC4 Nuclear Import
Open accessAbstract
Different signal-regulated serine/threonine kinases phosphorylate class II histone deacetylases (HDACs) to promote nuclear export, cytosolic accumulation, and activation of gene transcription. However, little is known about mechanisms operating in the opposite direction, which, possibly through phosphatases, should promote class II HDACs nuclear entry and subsequent gene repression. Here we show that HDAC4 forms a complex with the PP2A holoenzyme Cα, Aα, B/PR55α. In vitro and in vivo binding studies demonstrate that the N-terminus of HDAC4 interacts with the catalytic subunit of PP2A. HDAC4 is dephosphorylated by PP2A and experiments using okadaic acid or RNA interference have revealed that PP2A controls HDAC4 nuclear import. Moreover, we identified serine 298 as a putative phosphorylation site important for HDAC4 nuclear import. The HDAC4 mutant mimicking phosphorylation of serine 298 is defective in nuclear import. Mutation of serine 298 to alanine partially rescues the defect in HDAC4 nuclear import observed in cells with down-regulated PP2A. These observations suggest that PP2A, via the dephosphorylation of multiple serines including the 14-3-3 binding sites and serine 298, controls HDAC4 nuclear import.
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“Cytoplasmic localization of HDAC4 is maintained by HDAC phosphorylation, suppressing the binding of the transcription factor MEF2,141 whereas HDAC4 dephosphorylation by calcineurin allows nuclear translocation.142”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [142]
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“In contrast, dephosphorylation of HDAC4 by calcineurin allows nuclear translocation.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [57]
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“142 Nuclear HDAC4 functions as a transcriptional repressor, downregulating the expression of numerous plasticity-related genes, that may mediate effects on learning and memory impairment in mice.”
BackgroundGuo, W., Shan, B., Klingsberg, R. C., Qin, X., & Lasky, J. A. (2009) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00128.2009 · Cited by 218
Metadata
- Authors
- Paroni, G., Cernotta, N., Dello Russo, C., Gallinari, P., Pallaoro, M., Foti, C., Talamo, F., Orsatti, L., Steinkühler, C., & Brancolini, C.
- Affiliations
- University of Udine (IT)
- IRBM/Merck Research Laboratories Rome, 00040 Pomezia, Italy
- Venue
- Molecular Biology of the Cell
- Published
- 2008-02
- Volume
- 19
- Issue
- 2
- Pages
- 655-667
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC2230598
- OpenAlex
- W2116685428
- Cited by
- 126
- References
- 49
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 10 · 2023: 6 · 2022: 8 · 2021: 7 · 2020: 6 · 2019: 4 · 2018: 3 · 2017: 7 · 2016: 10 · 2015: 9 · 2014: 8 · 2013: 9 · 2012: 6
- FWCI
- 3.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Biology of the Cell (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System (University of Udine) (submittedVersion)
- Funders
- International Center for Genetic Engineering and Biotechnology
- Associazione Italiana per la Ricerca sul Cancro
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- protein phosphatase 2A, HDAC4, class II histone deacetylases, nuclear import, dephosphorylation, PP2A catalytic subunit, gene repression, protein phosphatase
- MeSH terms
- Amino Acid Sequence, Cell Line, Cell Nucleus, Histone Deacetylases, Humans, Molecular Sequence Data, Phosphorylation, Protein Binding, Repressor Proteins, Serine, Electrophoresis, Gel, Two-Dimensional, Myogenic Regulatory Factors, Okadaic Acid, Caspases, Active Transport, Cell Nucleus, Protein Interaction Mapping, Mutant Proteins, Protein Phosphatase 2
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