Human Molecular Genetics Advance Access originally published online on February 22, 2007
Human Molecular Genetics 2007 16(7):848-864; doi:10.1093/hmg/ddm030
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CHIP and HSPs interact with ß-APP in a proteasome-dependent manner and influence Aß metabolism
1 Department of Neurology, Caritas St Elizabeth's Medical Center, Tufts University School of Medicine, 736 Cambridge Street, Boston, MA 02135, USA, 2 Boston Biomedical Research Institute, Watertown, MA 02472, USA, 3 Department of Molecular Cellular and Developmental Biology, UCSB, Santa Barbara, CA 93106, USA, 4 ENH Research Institute, 1001 University Place, Evanston, IL 60201, USA, 5 The Cardiovascular Institute, Loyola University Medical Center, IL 60153, USA and 6 Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, NC 27599, USA
* To whom correspondence should be addressed at: Tel: +1 6177892685; Fax: +1 6177895177; E-mail: henry.querfurth{at}tufts.edu
Received February 9, 2007; Accepted February 12, 2007
The C-terminus Hsp70 interacting protein (CHIP) has dual function as both co-chaperone and ubiquitin ligase. CHIP is increasingly implicated in the biology of polyglutamine expansion disorders, Parkinson's disease and tau protein in Alzheimer's disease. We investigated the involvement of CHIP in the metabolism of the ß-amyloid precursor protein and its derivative ß-amyloid (Aß). Using immunoprecipitation, fluorescence localization and crosslinking methods, endogenous CHIP and ßAPP interact in brain and cultured skeletal myotubes as well as when they are expressed in stable HEK cell lines. Their interaction is confined to Golgi and ER compartments. In the presence of the proteasome inhibitor with MG132, endogenous and expressed ßAPP levels are significantly increased and accordingly, the interaction with CHIP enhanced. Concurrently, levels of Hsp70 were most consistently induced by proteasome inhibition among the various heat shock proteins (HSPs) tested. Thus, complexes of CHIP, Hsp70 and holo-ßAPP (as well as C-terminal fragments) were stabilized by the action of MG132. Moreover, CHIP itself is shown to both increase cellular holo-ßAPP levels and protect it from oxidative stress and degradation. Interestingly, CHIP also promotes the association of ubiquitin with ßAPP, implying that a smaller pool of ßAPP is destined for proteasomal processing. In neuronal cultures, CHIP and Hsp70/90 expression reduce steady-state cellular Aß levels and hasten its degradation in pulse-chase experiments. The functional significance of CHIP and HSP interactions, especially with Hsp70, was tested using siRNA and in neuronal cells where protection from Aß-induced toxicity is shown. We conclude that CHIP, as a bimolecular switch, interacts with HSP to stabilize normal holo-ßAPP on the one hand while also assisting in the ubiquitination of a subpopulation of ßAPP molecules that are destined for proteasome degradation. CHIP also hastens the clearance of Aß in a manner consistent with its known neuroprotective properties.
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