title: 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.
authors.affiliation: Cognosci, Inc., Research Triangle Park, NC 27709, USA.
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Christensen
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Ohkubo
authors.forename: Jessica
authors.initials: J
authors.lastname: Oddo
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Van Kanegan
authors.forename: Jessica
authors.initials: J
authors.lastname: Neil
authors.forename: Fengqiao
authors.initials: F
authors.lastname: Li
authors.forename: Carol A
authors.initials: CA
authors.lastname: Colton
authors.forename: Michael P
authors.initials: MP
authors.lastname: Vitek
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D004268:DNA-Binding Proteins; D015536:Down-Regulation / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D056488:Histone Chaperones / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018716:Molecular Mimicry / Q000276:immunology*; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding / Q000276:immunology; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D001057:Apolipoproteins E; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D018836:Inflammation Mediators; D015513:Oncogene Proteins; D010446:Peptide Fragments; C513473:SET protein, human; C557500:SET protein, mouse; D014157:Transcription Factors; D054648:Protein Phosphatase 2