Title

CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival.

Journal

The Journal of biological chemistry

Volume

279

Issue

None

Pages

4869-76

Date

2004-02-06

Authors

Shimura H | Gygi SP | Schwartz D | Kosik KS

These data indicated that phosphorylation of PP2A dephosphorylation sites is an important recognition signal for ubiquitination. We used 200 μg of amino-terminal His-tagged full-length recombinant human tau in an in vitro phosphorylation reaction with GSK-3Beta. When phosphorylated, the tau protein reacted on immunoblots with PHF1 (25, 26) and AT8 (24), indicating that at least sites Ser202, Thr205, Ser396, and Ser404 were phosphorylated. Following GSK-3Beta incubation, this tau served as an excellent substrate for in vitro ubiquitination using UbcH5B and the cofactor fraction from AD tau immunoprecipitates (Fig. 2a). This finding suggested that GSK-3Beta can place phosphates on tau that create recognition sites for an E3 Ub ligase.

These data suggest a model by which phosphorylated tau is bound to a chaperone and the complex is recognized by the E3 Ub ligase CHIP. We further examined whether recombinant GST-CHIP ubiquitinates phosphorylated tau in vitro in the presence of UbcH5B and Hsc70. Ubiquitination of phosphorylated tau was detected as high molecular weight bands by immunoblotting with 5E2 in the presence of UbcH5B and Hsc70 (Fig. 2e).

This result strongly suggested that the E2 conjugating enzyme for tau ubiquitination is UbcH5B.

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