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The highly heat-inducible HspA6 and the thermolabile DnaJB5 are potent regulators of heat shock transcription factor 1 activity

Year: 2026
Type: article
Abstract: In response to proteotoxic stress the central regulator of the heat shock response (HSR) in mammalian cells, Hsf1, trimerizes, binds DNA, and drives transcription of heat shock genes. We previously showed that Hsc70 (HspA8) assisted by its J-domain protein (JDP) cochaperone DnaJB1 dissociates Hsf1 from DNA by monomerizing the trimeric Hsf1 and thereby attenuates the HSR. Whether this feedback mechanism is specific to the HspA8–DnaJB1 pair or instead reflects a broader, isoform- and JDP-selective Hsp70 network controlling Hsf1 remained unresolved. Here, we demonstrate that of all cytonuclear Hsp70s the highly heat-inducible HspA6 is most efficient in monomerizing Hsf1 in the presence of DnaJB1 and of all cytonuclear class A and class B JDPs, only DnaJB1, DnaJB4, and DnaJB5 assist in Hsf1 monomerization. Whereas cooperation of HspA6 and HspA8 with DnaJB1 and DnaJB4 absolutely depends on Hsp70s’ C-terminal glutamate-glutamate-valine-glutamate (EEVD)-motif, cooperation with DnaJB5 does not. Consistent with these data, overproduction of EEVD-deleted HspA8 and HspA6 down-regulate the HSR in HeLa cells. DnaJB5 knockdown reduces HspA8–Hsf1 interaction under nonstress conditions revealing DnaJB5 as major targeting factor for HspA8 binding to Hsf1. On temperature upshift DnaJB5 partially unfolds and partitions into insoluble cell fractions, suggesting it is a thermosensor that allows for increased Hsf1 activity by reducing HspA8’s ability to monomerize Hsf1. During ongoing heat shock, upregulated HspA6 and HspA8 then limit the HSR presumably targeted by heat-induced DnaJB1. HspA6 knock-down and overproduction in HeLa cells suggest that HspA6 functions in preventing an overshoot of the HSR.
DOI: 10.1073/pnas.2623767123
Language: English
Open Access status: hybrid
OpenAlex ID: W7225733849
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Cites: 43
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