Apolipoprotein E and Peptide Mimetics Modulate Inflammation by Binding the SET Protein and Activating Protein Phosphatase 2A
Abstract
The molecular mechanism by which apolipoprotein E (apoE) suppresses inflammatory cytokine and NO production is unknown. Using an affinity purification approach, we found that peptide mimetics of apoE, derived from its receptor binding domain residues 130–150, bound to the SET protein, which is a potent physiological inhibitor of protein phosphatase 2A (PP2A). Both holo-apoE protein and apoE-mimetic peptides bound to the C-terminal region of SET, which is then associated with an increase in PP2A-mediated phosphatase activity. As physiological substrates for PP2A, the LPS-induced phosphorylation status of signaling MAPK and Akt kinase is reduced following treatment with apoE-mimetic peptides. On the basis of our previous report, in which apoE-mimetic peptides reduced I-κB kinase and NF-κB activation, we also demonstrate a mechanism for reduced production of inducible NO synthase protein and its NO product. These data provide evidence for a novel molecular mechanism by which apoE and apoE-mimetic peptides antagonize SET, thereby enhancing endogenous PP2A phosphatase activity, which reduces levels of phosphorylated kinases, signaling, and inflammatory response.
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APOE mimetics (small peptides homologous to the receptor-binding region of APOE) have been shown to prevent microglial reaction in vitro, as well as Aβ deposition and associated memory deficits in APOE4 plaque-depositing mice.
“Such APOE mimetics have been shown to prevent microglial reaction in vitro, as well as Aβ deposition and associated memory deficits in APOE4 plaque-depositing mice195,196.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [195]
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- Authors
- Christensen, D. J., Ohkubo, N., Oddo, J., Van Kanegan, M. J., Neil, J., Li, F., Colton, C. A., & Vitek, M. P.
- Affiliations
- Duke University (US)
- Cognosci (United States) (US)
- Cognosci, Inc. , Research Triangle Park, NC 27709
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-02
- Volume
- 186
- Issue
- 4
- Pages
- 2535-2542
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1876581925
- Cited by
- 125
- References
- 4
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 4 · 2023: 9 · 2022: 8 · 2021: 2 · 2020: 5 · 2019: 6 · 2018: 7 · 2017: 15 · 2016: 11 · 2015: 11 · 2014: 11 · 2013: 7 · 2012: 14
- FWCI
- 5.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R44AG020473)
- National Cancer Institute (R43CA137941)
- National Institute of Allergy and Infectious Diseases (R43AI072864)
- National Institute of Diabetes and Digestive and Kidney Diseases (R41DK075161)
- National Institute of Neurological Disorders and Stroke (R44NS052920)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- apolipoprotein E, peptidomimetics, SET protein, protein phosphatase 2A, inflammation, MAPK phosphorylation, Akt kinase, inducible nitric oxide synthase, nitric oxide production, NF-κB activation, IκB kinase, lipopolysaccharide, receptor binding domain, kinase dephosphorylation
- MeSH terms
- Amino Acid Sequence, Animals, Apolipoproteins E, Cell Line, DNA-Binding Proteins, Enzyme Activation, Humans, Male, Mice, Inbred C57BL, Molecular Sequence Data, Peptide Fragments, Protein Binding, Transcription Factors, Signal Transduction, Oncogene Proteins, Down-Regulation, Up-Regulation, Molecular Mimicry, Inflammation Mediators, Mice, Protein Phosphatase 2, Histone Chaperones
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