Human Molecular Genetics Advance Access originally published online on May 6, 2005
Human Molecular Genetics 2005 14(12):1659-1669; doi:10.1093/hmg/ddi174
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
HspB8, a small heat shock protein mutated in human neuromuscular disorders, has in vivo chaperone activity in cultured cells
1Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, 9 rue McMahon, Québec, Canada G1R 2J6 and 2Universidad Centroccidental Lisandro Alvarado, Decanato de Medicina, Departamento de Morfología, Sección de Anatomía Microscópica, Avenida Libertador con Avenida Andrés Bello, Barquisimeto, Estado Lara, Venezuela
* To whom correspondence should be addressed: Tel: +418 6915281; Fax: +418 6915439; Email: jacques.landry{at}med.ulaval.ca
Received March 1, 2005; Revised April 19, 2005; Accepted April 26, 2005
The family of small heat shock proteins (sHsp) is composed of 10 members in mammals, four of which are found mutated in diseases associated with the accumulation of protein aggregates. Though many sHsp have demonstrated molecular chaperone activity in vitro in cell-free conditions, their activity in vivo in the normal cellular context remains unclear. In the present study, we investigated the capacity of the sHsp, HspB8/Hsp22, to prevent protein aggregation in the cells using the polyglutamine protein Htt43Q as a model. In control conditions, Htt43Q accumulated in perinuclear inclusions composed of SDS-insoluble aggregates. Co-transfected with Htt43Q, HspB8 became occasionally trapped within the inclusions; however, in most cells, HspB8 blocked inclusion formation. Biochemical analyses indicated that HspB8 inhibited the accumulation of SDS-insoluble Htt43Q as efficiently as Hsp40 which was taken as a positive control. Htt43Q then accumulated in the SDS-soluble fraction, provided that protein degradation was blocked by proteasome and autophagy inhibitors. In contrast, the other sHsp Hsp27/HspB1 and 
B-crystallin/HspB5 had no effect. This suggested that HspB8 functions as a molecular chaperone, maintaining Htt43Q in a soluble state competent for rapid degradation. Analyses of Hsp27–HspB8 chimeric proteins indicated that the C-terminal domain of HspB8 contains the specific sequence necessary for chaperone activity. Missense mutations in this domain at lysine 141, which are found in human motor neuropathies, significantly reduced the chaperone activity of the protein. A decrease in the HspB8 chaperone activity may therefore contribute to the development of these diseases.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Carra, S. J. Seguin, H. Lambert, and J. Landry HspB8 Chaperone Activity toward Poly(Q)-containing Proteins Depends on Its Association with Bag3, a Stimulator of Macroautophagy J. Biol. Chem., January 18, 2008; 283(3): 1437 - 1444. [Abstract] [Full Text] [PDF]
|
|