title: BECN1/Beclin 1 is recruited into lipid rafts by prion to activate autophagy in response to amyloid β 42.
abstract: Prion protein (PRNP) has been implicated in various types of neurodegenerative diseases. Although much is known about prion diseases, the function of cellular PRNP remains cryptic. Here, we show that PRNP mediates amyloid β1–42 (Aβ42)-induced autophagy activation through its interaction with BECN1. Treatment with Aβ42 enhanced autophagy flux in neuronal cells. Aβ42-induced autophagy activation, however, was impaired in prnp-knockout primary cortical neurons and Prnp-knockdown or prnp-knockout neuronal cells. Immunoprecipitation assays revealed that PRNP interacted with BECN1 via the BCL2-binding domain of BECN1. This interaction promoted the subcellular localization of BECN1 into lipid rafts of the plasma membrane and enhanced activity of PtdIns3K (whose catalytic subunit is termed PIK3C3, mammalian ortholog of yeast VPS34) in lipid rafts by generating PtdIns3P in response to Aβ42. Further, the levels of lipid rafts that colocalized with BECN1, decreased in the brains of aged C57BL/6 mice, as did PRNP. These results suggested that PRNP interacts with BECN1 to recruit the PIK3C3 complex into lipid rafts and thus activates autophagy in response to Aβ42, defining a novel role of PRNP in the regulation of autophagy.
authors.forename: Jihoon
authors.initials: J
authors.lastname: Nah
authors.forename: Jong-Ok
authors.initials: JO
authors.lastname: Pyo
authors.forename: Sunmin
authors.initials: S
authors.lastname: Jung
authors.forename: Seung-Min
authors.initials: SM
authors.lastname: Yoo
authors.forename: Tae-In
authors.initials: TI
authors.lastname: Kam
authors.forename: JaeWoong
authors.initials: J
authors.lastname: Chang
authors.forename: Jonghee
authors.initials: J
authors.lastname: Han
authors.forename: Seong
authors.initials: S
authors.lastname: Soo A An
authors.forename: Takashi
authors.initials: T
authors.lastname: Onodera
authors.forename: Yong-Keun
authors.initials: YK
authors.lastname: Jung
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D057809:HEK293 Cells; D006801:Humans; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D000072002:Prion Proteins; D011328:Prions / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; C512656:PRNP protein, human; D010446:Peptide Fragments; D000072002:Prion Proteins; D011328:Prions; C075222:amyloid beta-protein (1-42)