title: Regulation of the cytoplasmic quality control protein degradation pathway by BAG2.
abstract: The cytoplasm is protected against the perils of protein misfolding by two mechanisms: molecular chaperones (which facilitate proper folding) and the ubiquitin-proteasome system, which regulates degradation of misfolded proteins. CHIP (carboxyl terminus of Hsp70-interacting protein) is an Hsp70-associated ubiquitin ligase that participates in this process by ubiquitylating misfolded proteins associated with cytoplasmic chaperones. Mechanisms that regulate the activity of CHIP are, at present, poorly understood. Using a proteomics approach, we have identified BAG2, a previously uncharacterized BAG domain-containing protein, as a common component of CHIP holocomplexes in vivo. Binding assays indicate that BAG2 associates with CHIP as part of a ternary complex with Hsc70, and BAG2 colocalizes with CHIP under both quiescent conditions and after heat shock. In vitro and in vivo ubiquitylation assays indicate that BAG2 is an efficient and specific inhibitor of CHIP-dependent ubiquitin ligase activity. This activity is due, in part, to inhibition of interactions between CHIP and its cognate ubiquitin-conjugating enzyme, UbcH5a, which may in turn be facilitated by ATP-dependent remodeling of the BAG2-Hsc70-CHIP heterocomplex. The association of BAG2 with CHIP provides a cochaperone-dependent regulatory mechanism for preventing unregulated ubiquitylation of misfolded proteins by CHIP.
authors.affiliation: Carolina Cardiovascular Biology Center and the Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599-7126, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Dai
authors.forename: Shu-Bing
authors.initials: SB
authors.lastname: Qian
authors.forename: Hui-Hua
authors.initials: HH
authors.lastname: Li
authors.forename: Holly
authors.initials: H
authors.lastname: McDonough
authors.forename: Christoph
authors.initials: C
authors.lastname: Borchers
authors.forename: David
authors.initials: D
authors.lastname: Huang
authors.forename: Shinichi
authors.initials: S
authors.lastname: Takayama
authors.forename: J Michael
authors.initials: JM
authors.lastname: Younger
authors.forename: Hong Yu
authors.initials: HY
authors.lastname: Ren
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Cyr
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000595:Amino Acid Sequence; D002460:Cell Line; D002843:Chromatin / Q000737:chemistry; D047369:Chromatin Immunoprecipitation; D003593:Cytoplasm / Q000378:metabolism*; D029721:Drosophila Proteins / Q000737:chemistry; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D033862:Iron-Binding Proteins / Q000737:chemistry; D013058:Mass Spectrometry; D008954:Models, Biological; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D013997:Time Factors; D014162:Transfection; D025801:Ubiquitin / Q000737:chemistry; D044763:Ubiquitin-Conjugating Enzymes / Q000737:chemistry; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: C492980:BAG2 protein, human; C108740:Chi protein, Drosophila; D002843:Chromatin; D029721:Drosophila Proteins; D018840:HSP70 Heat-Shock Proteins; D033862:Iron-Binding Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D025801:Ubiquitin; D000255:Adenosine Triphosphate; C097308:UBE2D1 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; D005982:Glutathione Transferase; D046988:Proteasome Endopeptidase Complex