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J. Biol. Chem., Vol. 283, Issue 3, 1437-1444, January 18, 2008

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HspB8 Chaperone Activity toward Poly(Q)-containing Proteins Depends on Its Association with Bag3, a Stimulator of Macroautophagy^*

From the Centre de Recherche en Cancérologie and Département de Médecine, Université Laval, Québec G1R 2J6, Canada

Mutations in HspB8, a member of the B group of heat shock proteins (Hsp), have been associated with human neuromuscular disorders. However, the exact function of HspB8 is not yet clear. We previously demonstrated that overexpression of HspB8 in cultured cells prevents the accumulation of aggregation-prone proteins such as the polyglutamine protein Htt43Q. Here we report that HspB8 forms a stable complex with Bag3 in cells and that the formation of this complex is essential for the activity of HspB8. Bag3 overexpression resulted in the accelerated degradation of Htt43Q, whereas Bag3 knockdown prevented HspB8-induced Htt43Q degradation. Additionally, depleting Bag3 caused a reduction in the endogenous levels of LC3-II, a key molecule involved in macroautophagy, whereas overexpressing Bag3 or HspB8 stimulated the formation LC3-II. These results suggested that the HspB8-Bag3 complex might stimulate the degradation of Htt43Q by macroautophagy. This was confirmed by the observation that treatments with macroautophagy inhibitors significantly decreased HspB8- and Bag3-induced degradation of Htt43Q. We conclude that the HspB8 activity is intrinsically dependent on Bag3, a protein that may facilitate the disposal of doomed proteins by stimulating macroautophagy.

Received for publication, July 31, 2007 , and in revised form, October 17, 2007.

^* This work was supported by Canadian Institutes of Health Research Grant MT-7088 and the Canada Research Chair in Stress Signal Transduction. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Current address: Dept. of Radiation and Stress Cell Biology, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands.

² To whom correspondence should be addressed: Centre de Recherche, L'Hôtel-Dieu de Québec, 9 rue McMahon, Québec G1R 2J6, Canada. Tel.: 418-691-5281; Fax: 418-691-5439; E-mail: jacques.landry{at}med.ulaval.ca.

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