title: WW domain of BAG3 is required for the induction of autophagy in glioma cells.
abstract: Autophagy is an evolutionarily conserved, selective degradation pathway of cellular components that is important for cell homeostasis under healthy and pathologic conditions. Here we demonstrate that an increase in the level of BAG3 results in stimulation of autophagy in glioblastoma cells. BAG3 is a member of a co-chaperone family of proteins that associates with Hsp70 through a conserved BAG domain positioned near the C-terminus of the protein. Expression of BAG3 is induced by a variety of environmental changes that cause stress to cells. Our results show that BAG3 overexpression induces autophagy in glioma cells. Interestingly, inhibition of the proteasome caused an increase in BAG3 levels and induced autophagy. Further analysis using specific siRNA against BAG3 suggests that autophagic activation due to proteosomal inhibition is mediated by BAG3. Analyses of BAG3 domain mutants suggest that the WW domain of BAG3 is crucial for the induction of autophagy. BAG3 overexpression also increased the interaction between Bcl2 and Beclin-1, instead of disrupting them, suggesting that BAG3 induced autophagy is Beclin-1 independent. These observations reveal a novel role for the WW domain of BAG3 in the regulation of autophagy.
authors.affiliation: Department of Neuroscience and Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Nana
authors.initials: N
authors.lastname: Merabova
authors.forename: Ilker Kudret
authors.initials: IK
authors.lastname: Sariyer
authors.forename: A Sami
authors.initials: AS
authors.lastname: Saribas
authors.forename: Tijana
authors.initials: T
authors.lastname: Knezevic
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gordon
authors.forename: M Caterina
authors.initials: MC
authors.lastname: Turco
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rosati
authors.forename: Michael
authors.initials: M
authors.lastname: Weaver
authors.forename: Jacques
authors.initials: J
authors.lastname: Landry
authors.forename: Kamel
authors.initials: K
authors.lastname: Khalili
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D002478:Cells, Cultured; D005910:Glioma / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; C491997:BECN1 protein, human; D000071186:Beclin-1; D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D046988:Proteasome Endopeptidase Complex