CHIP: a link between the chaperone and proteasome systems

Abstract

CHIP, carboxy terminus of Hsc70 interacting protein, is a cytoplasmic protein whose amino acid sequence is highly conserved across species. It is most highly expressed in cardiac and skeletal muscle and brain. The primary amino acid sequence is characterized by 3 domains, a tetratricopeptide repeat (TPR) domain at its amino terminus, a U-box domain at its carboxy terminus, and an intervening charged domain. CHIP interacts with the molecular chaperones Hsc70-Hsp70 and Hsp90 through its TPR domain, whereas its U-box domain contains its E3 ubiquitin ligase activity. Its interaction with these molecular chaperones results in client substrate ubiquitylation and degradation by the proteasome. Thus, CHIP acts to tilt the folding-refolding machinery toward the degradative pathway, and it serves as a link between the two. Because protein degradation is required for healthy cellular function, CHIP's ability to degrade proteins that are the signature of disease, eg, ErbB2 in breast and ovarian cancers, could prove to be a point of therapeutic intervention.

Phosphorylation of CHIP at Ser20 by Cdk5 promotes tAIF-mediated neuronal death

“…Recently, CHIP has been implicated in progression of the pathophysiological conditions of various neurodegenerative diseases. 8,9,11,12,28,46,47 However, the molecular mechanisms regulating the functions of CHIP in these pathophysiologic conditions are not clearly elucidated. In the present study, we identify that CHIP and Cdk5 act as critical factors to regulate the level of the toxic protein, tAIF, during oxidative stress-induced neuronal death.…”

“…CHIP is composed of three major domains: (1) an aminoterminal three tetratricopeptide repeat (TPR) domain interacting with Hsc/Hsp70 and Hsp90, (2) a highly charged central domain with unknown functions and (3) a carboxyl-terminal U-box domain conferring E3 ubiquitin ligase activity. [8][9][10] Based on these domains, it has been indicated that CHIP has a crucial role as a molecular co-chaperone in the maintenance of protein homeostasis during cellular stress and recovery. 8,[11][12][13] Indeed, CHIP has been demonstrated to serve as a crucial catalyst for ubiquitination of Hsp70 client proteins targeting for proteasome-dependent degradation.…”

“…[8][9][10] Based on these domains, it has been indicated that CHIP has a crucial role as a molecular co-chaperone in the maintenance of protein homeostasis during cellular stress and recovery. 8,[11][12][13] Indeed, CHIP has been demonstrated to serve as a crucial catalyst for ubiquitination of Hsp70 client proteins targeting for proteasome-dependent degradation. 11 The function of CHIP with its molecular chaperones has been well documented to reduce cellular toxicity associated with several neurodegenerative diseases.…”

CHIP promotes the degradation of mutant SOD1 by reducing its interaction with VCP and S6/S6′ subunits of 26S proteasome

“…CHIP functions as a co-chaperone of Hsp70, interacting with the chaperones through its TPR (tetratricopeptide repeat) domain, and also possesses an E3 ligase activity which is mediated by the U-box domain (McDonough and Patterson 2003). Thus CHIP can provide a link between the chaperones and UPS and probably regulates the balance between protein refolding and degradation in the cells.…”

“…Findings that CHIP interacts with the S5a subunit of proteasomes and co-localizes with the proteasomes in cells have led to a suggestion that CHIP also participates in substrate delivery to the proteasomes (McDonough and Patterson 2003). Bag-1, another cochaperone of Hsp70, has also been implicated in the sorting of substrates to proteasomes (Demand et al 2001;Alberti et al 2002).…”