An isotype-specific phosphorylation of Hsp90 rewires co-chaperone regulations.

The molecular chaperone Hsp90 is a major protein folding factor in the cytosol of eukaryotic cells. Its conformational cycle is regulated by various co-chaperones and post-translational modifications (PTMs) such as phosphorylation. Most of the phosphorylation sites are conserved between the 2 isoforms of human Hsp90, Hsp90α and Hsp90β. The analysis of the function of these sites has revealed general functional principles of Hsp90. To what extent isoform-specific phosphorylation regulates Hsp90 function is less well understood. Here, we explore the effect of the phosphorylation of a residue (threonine 446) specific for the constitutionally active isoform Hsp90β. Since T446 is bioinformatically predicted to be phosphorylated by kinases regulating the intrinsic stress response (ISR), this modification links Hsp90 function to the ISR status of the cell in an isotype-specific manner which renders Hsp90 unresponsive to the co-chaperone-mediated modulation of its ATPase activity and consequently affects client maturation. Hsp90β reverts to baseline ATPase-driven chaperoning activity which is no longer intensively regulated by co-chaperones and results in the rewiring of Hsp90-mediated protein quality control.