title: BAG3 induces the sequestration of proteasomal clients into cytoplasmic puncta: implications for a proteasome-to-autophagy switch.
abstract: Eukaryotic cells use autophagy and the ubiquitin-proteasome system as their major protein degradation pathways. Upon proteasomal impairment, cells switch to autophagy to ensure proper clearance of clients (the proteasome-to-autophagy switch). The HSPA8 and HSPA1A cochaperone BAG3 has been suggested to be involved in this switch. However, at present it is still unknown whether and to what extent BAG3 can indeed reroute proteasomal clients to the autophagosomal pathway. Here, we show that BAG3 induces the sequestration of ubiquitinated clients into cytoplasmic puncta colabeled with canonical autophagy linkers and markers. Following proteasome inhibition, BAG3 upregulation significantly contributes to the compensatory activation of autophagy and to the degradation of the (poly)ubiquitinated proteins. BAG3 binding to the ubiquitinated clients occurs through the BAG domain, in competition with BAG1, another BAG family member, that normally directs ubiquitinated clients to the proteasome. Therefore, we propose that following proteasome impairment, increasing the BAG3/BAG1 ratio ensures the "BAG-instructed proteasomal to autophagosomal switch and sorting" (BIPASS).
authors.affiliation: Department of Cell Biology; University Medical Center Groningen; University of Groningen; Groningen, The Netherlands.
authors.forename: Melania
authors.initials: M
authors.lastname: Minoia
authors.affiliation: Department of Cell Biology; University Medical Center Groningen; University of Groningen; Groningen, The Netherlands; Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB); Università degli Studi di Milano; Centro di Eccellenza sulle Patologie Neurodegenerative (CEND); Milano, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Boncoraglio
authors.affiliation: Dipartimento di Scienze Biomediche; Metaboliche e Neuroscienze; Università degli Studi di Modena e Reggio Emilia; Modena, Italy.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Vinet
authors.affiliation: Dipartimento di Scienze Biomediche; Metaboliche e Neuroscienze; Università degli Studi di Modena e Reggio Emilia; Modena, Italy.
authors.forename: Federica F
authors.initials: FF
authors.lastname: Morelli
authors.affiliation: Department of Cell Biology; University Medical Center Groningen; University of Groningen; Groningen, The Netherlands.
authors.forename: Jeanette F
authors.initials: JF
authors.lastname: Brunsting
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB); Università degli Studi di Milano; Centro di Eccellenza sulle Patologie Neurodegenerative (CEND); Milano, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Poletti
authors.affiliation: Departments of Cell Biology and Histology; University of Amsterdam; Academic Medical Center; Amsterdam, The Netherlands.
authors.forename: Sabine
authors.initials: S
authors.lastname: Krom
authors.affiliation: Departments of Cell Biology and Histology; University of Amsterdam; Academic Medical Center; Amsterdam, The Netherlands.
authors.forename: Eric
authors.initials: E
authors.lastname: Reits
authors.affiliation: Department of Cell Biology; University Medical Center Groningen; University of Groningen; Groningen, The Netherlands.
authors.forename: Harm H
authors.initials: HH
authors.lastname: Kampinga
authors.affiliation: Department of Cell Biology; University Medical Center Groningen; University of Groningen; Groningen, The Netherlands; Dipartimento di Scienze Biomediche; Metaboliche e Neuroscienze; Università degli Studi di Modena e Reggio Emilia; Modena, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Carra
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D014157:Transcription Factors / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; C091732:BCL2-associated athanogene 1 protein; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex
keywords: BAG3; autophagy linkers; proteasome inhibition; ubiquitinated proteins