| Abstract |
The activity of protein phosphatase 2 A containing the B55 regulatory subunit (PP2A:B55) is tightly controlled by various positive and negative modulators. IER family proteins function as adapters by simultaneously binding the B55 subunit and specific substrates, thereby promoting their dephosphorylation by PP2A:B55. Here, we report that the B55-binding domain of IER proteins shares significant amino acid homology with the SERTA domain of the SERTAD family. All SERTAD family members-SERTAD1, SERTAD2, SERTAD3, SERTAD4, and CDCA4-bind to B55-containing PP2A complexes. Among these, SERTAD1 induces dephosphorylation of heat shock factor HSF1 at Ser320, leading to suppression of HSF1 transcriptional activity. This regulatory function of SERTAD1 requires its nuclear localization and interaction with both HSF1 and the B55 subunit. In contrast, the PP2A:B55 adapter IER5 promotes dephosphorylation of HSF1 at Ser303, Ser307, and Ser320, resulting in enhanced HSF1 activity. The differential dephosphorylation patterns mediated by SERTAD1 and IER5 are attributed to structural differences in helix 1 of their respective B55-binding domains. These findings identify SERTAD1 as a novel PP2A:B55 adapter and highlight the role of the B55-binding domain in governing site-specific substrate dephosphorylation.
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