A DNAJB chaperone subfamily with HDAC-dependent activities suppresses toxic protein aggregation.
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.
Department of Cell Biology, Section of Radiation and Stress Cell Biology, University Medical Center Groningen and University of Groningen, 9700 RB Groningen, The Netherlands.
Jurre
J
Hageman
Maria A
MA
Rujano
Maria A W H
MA
van Waarde
Vaishali
V
Kakkar
Ron P
RP
Dirks
Natalia
N
Govorukhina
Henderika M J
HM
Oosterveld-Hut
Nicolette H
NH
Lubsen
Harm H
HH
Kampinga
D000818:Animals; D002460:Cell Line; D050956:HSP40 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism / Q000502:physiology; D018869:Heat-Shock Response; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D010455:Peptides / Q000378:metabolism; D057165:Proteostasis Deficiencies / Q000378:metabolism; D014982:Xenopus laevis
D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D010455:Peptides; C097188:polyglutamine; D006655:Histone Deacetylases