BAG-2 acts as an inhibitor of the chaperone-associated ubiquitin ligase CHIP.
Cellular protein quality control involves a close interplay between molecular chaperones and the ubiquitin/proteasome system. We recently identified a degradation pathway, on which the chaperone Hsc70 delivers chaperone clients, such as misfolded forms of the cystic fibrosis transmembrane conductance regulator (CFTR), to the proteasome. The cochaperone CHIP is of central importance on this pathway, because it acts as a chaperone-associated ubiquitin ligase. CHIP mediates the attachment of a ubiquitin chain to a chaperone-presented client protein and thereby stimulates its proteasomal degradation. To gain further insight into the function of CHIP we isolated CHIP-containing protein complexes from human HeLa cells and analyzed their composition by peptide mass fingerprinting. We identified the Hsc70 cochaperone BAG-2 as a main component of CHIP complexes. BAG-2 inhibits the ubiquitin ligase activity of CHIP by abrogating the CHIP/E2 cooperation and stimulates the chaperone-assisted maturation of CFTR. The activity of BAG-2 resembles that of the previously characterized Hsc70 cochaperone and CHIP inhibitor HspBP1. The presented data therefore establish multiple mechanisms to control the destructive activity of the CHIP ubiquitin ligase in human cells.
Arndt
Verena
V
Institute for Cell Biology, Rheinische Friedrich-Wilhelms-University Bonn, D-53121 Bonn, Germany.
Daniel
Christina
C
Nastainczyk
Wolfgang
W
Alberti
Simon
S
Höhfeld
Jörg
J
D000595:Amino Acid Sequence; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D019281:Dimerization; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D017510:Protein Folding; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
C492980:BAG2 protein, human; D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D010446:Peptide Fragments; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases