The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins
Chad A. Dickey, … , Francis Burrows, Leonard Petrucelli
Chad A. Dickey, … , Francis Burrows, Leonard Petrucelli
Published March 1, 2007
Citation Information: J Clin Invest. 2007;117(3):648-658. https://doi.org/10.1172/JCI29715.
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Research Article

The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins

Abstract

A primary pathologic component of Alzheimer’s disease (AD) is the formation of neurofibrillary tangles composed of hyperphosphorylated tau (p-tau). Expediting the removal of these p-tau species may be a relevant therapeutic strategy. Here we report that inhibition of Hsp90 led to decreases in p-tau levels independent of heat shock factor 1 (HSF1) activation. A critical mediator of this mechanism was carboxy terminus of Hsp70–interacting protein (CHIP), a tau ubiquitin ligase. Cochaperones were also involved in Hsp90-mediated removal of p-tau, while those of the mature Hsp90 refolding complex prevented this effect. This is the first demonstration to our knowledge that blockade of the refolding pathway promotes p-tau turnover through degradation. We also show that peripheral administration of a novel Hsp90 inhibitor promoted selective decreases in p-tau species in a mouse model of tauopathy, further suggesting a central role for the Hsp90 complex in the pathogenesis of tauopathies. When taken in the context of known high-affinity Hsp90 complexes in affected regions of the AD brain, these data implicate a central role for Hsp90 in the development of AD and other tauopathies and may provide a rationale for the development of novel Hsp90-based therapeutic strategies.

Authors

Chad A. Dickey, Adeela Kamal, Karen Lundgren, Natalia Klosak, Rachel M. Bailey, Judith Dunmore, Peter Ash, Sareh Shoraka, Jelena Zlatkovic, Christopher B. Eckman, Cam Patterson, Dennis W. Dickson, N. Stanley Nahman Jr., Michael Hutton, Francis Burrows, Leonard Petrucelli

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Figure 7

Phosphorylation at S262/S356 prevents ubiquitination and degradation of tau by either CHIP or Hsp90 inhibition, but does not abolish CHIP/Hsp90 binding, further implicating ubiquitination of p-tau by CHIP as a necessary component for Hsp90-mediated degradation.

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Phosphorylation at S262/S356 prevents ubiquitination and degradation of ...
(A) HEK293 cells transfected with either wild-type V5-tau or V5-tau harboring the double mutation of S262A/S356A were cotransfected with myc-CHIP, PAR-1, or both. V5 coimmunoprecipitation showed that CHIP bound to and greatly enhanced the polyubiquitination of wild-type tau; however, PAR-1 phosphorylation of tau prevented this interaction. Mutation of the S262 and S356 sites to alanine residues attenuated CHIP binding; however, ubiquitination activity was entirely abrogated. Inputs confirmed the hyperphosphorylation of wild-type tau at the S262/S356 residues in the presence of PAR-1. (B) HeLa cells expressing wild-type V5-tau were cotransfected with constitutively active GSK3β, PAR-1, or empty vector and then treated with EC102 or vehicle. In the absence of EC102, constutively active GSK3β promoted the phosphorylation of tau at S396/S404 relative to empty vector and PAR-1 promoted the phosphorylation of tau at S262/S356 relative to empty vector. In the presence of EC102, phosphorylated S396/S404 was dramatically reduced compared with treatment with vehicle, while phosphorylated S262/S356 was largely unaffected by drug treatment. (C) HeLa cells expressing wild-type V5-tau were cotransfected with constitutively active GSK3β or empty vector. Tau was then coimmunoprecipitated with the V5 antibody, and Hsp90 binding was assessed. Hsp90 bound more avidly to tau phosphorylated by constutively active GSK3β compared with cells transfected with vector alone.