HspB8 and Bag3: a new chaperone complex targeting misfolded proteins to macroautophagy.
Protein quality control involves molecular chaperones that recognize misfolded proteins thereby preventing their aggregation, and associated co-chaperones that modulate substrate sorting between renaturation and proteasomal degradation. We recently described a new chaperone complex that stimulates degradation of protein substrates by macroautophagy. The complex is formed of HspB8, a member of the HspB family of molecular chaperones, which is found mutated in neuromuscular diseases, and Bag3, a member of the co-chaperone family of Bag domain-containing proteins. In this complex, Bag3 was shown to be responsible for macroautophagy stimulation. Here we analyzed the role of the three Bag3 canonical protein interaction domains. We show that the proline-rich region is essential for the Bag3-mediated stimulation of mutated huntingtin clearance. Surprisingly, deletion of the BAG domain that mediates Bag3 interaction with Hsp70 and Blc-2, did not affect its activity. We propose that in the HspB8- Bag3 complex, HspB8 is responsible for recognizing the misfolded proteins whereas Bag3, at least in part through its proline-rich domain, might recruit and activate the macroautophagy machinery in close proximity to the chaperone-loaded substrates.
Carra
Serena
S
Centre de Recherche en Cancérologie and Département de Médecine, Université Laval, Québec, Canada.
Seguin
Samuel J
SJ
Landry
Jacques
J
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000502:physiology*; D006360:Heat-Shock Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D018832:Molecular Chaperones / Q000502:physiology; D046912:Multiprotein Complexes / Q000502:physiology; D011485:Protein Binding; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; C413214:HSPB8 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D017346:Protein Serine-Threonine Kinases