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. 2010 Feb 12;37(3):355-69.
doi: 10.1016/j.molcel.2010.01.001.

A DNAJB chaperone subfamily with HDAC-dependent activities suppresses toxic protein aggregation

Jurre Hageman  1 , Maria A Rujano, Maria A W H van Waarde, Vaishali Kakkar, Ron P Dirks, Natalia Govorukhina, Henderika M J Oosterveld-Hut, Nicolette H Lubsen, Harm H Kampinga
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Free article

A DNAJB chaperone subfamily with HDAC-dependent activities suppresses toxic protein aggregation

Jurre Hageman et al. Mol Cell. .
Free article

Abstract

Misfolding and aggregation are associated with cytotoxicity in several protein folding diseases. A large network of molecular chaperones ensures protein quality control. Here, we show that within the Hsp70, Hsp110, and Hsp40 (DNAJ) chaperone families, members of a subclass of the DNAJB family (particularly DNAJB6b and DNAJB8) are superior suppressors of aggregation and toxicity of disease-associated polyglutamine proteins. The antiaggregation activity is largely independent of the N-terminal Hsp70-interacting J-domain. Rather, a C-terminal serine-rich (SSF-SST) region and the C-terminal tail are essential. The SSF-SST region is involved in substrate binding, formation of polydisperse oligomeric complexes, and interaction with histone deacetylases (HDAC4, HDAC6, SIRT2). Inhibiting HDAC4 reduced DNAJB8 function. DNAJB8 is (de)acetylated at two conserved C-terminal lysines that are not involved in substrate binding, but do play a role in suppressing protein aggregation. Combined, our data provide a functional link between HDACs and DNAJs in suppressing cytotoxic protein aggregation.

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