CHIP-mediated stress recovery by sequential ubiquitination of substrates and Hsp70

Abstract

Exposure of cells to various stresses often leads to the induction of a group of proteins called heat shock proteins (HSPs, molecular chaperones). Hsp70 is one of the most highly inducible molecular chaperones, but its expression must be maintained at low levels under physiological conditions to permit constitutive cellular activities to proceed. Heat shock transcription factor 1 (HSF1) is the transcriptional regulator of HSP gene expression, but it remains poorly understood how newly synthesized HSPs return to basal levels when HSF1 activity is attenuated. CHIP (carboxy terminus of Hsp70-binding protein), a dual-function co-chaperone/ubiquitin ligase, targets a broad range of chaperone substrates for proteasomal degradation. Here we show that CHIP not only enhances Hsp70 induction during acute stress but also mediates its turnover during the stress recovery process. Central to this dual-phase regulation is its substrate dependence: CHIP preferentially ubiquitinates chaperone-bound substrates, whereas degradation of Hsp70 by CHIP-dependent targeting to the ubiquitin-proteasome system occurs when misfolded substrates have been depleted. The sequential catalysis of the CHIP-associated chaperone adaptor and its bound substrate provides an elegant mechanism for maintaining homeostasis by tuning chaperone levels appropriately to reflect the status of protein folding within the cytoplasm.

MKKS Is a Centrosome-shuttling Protein Degraded by Disease-causing Mutations via CHIP-mediated Ubiquitination

“…CHIP interacts with HSC70 and HSP90 through its amino-terminal TPR domain, and the ubiquitin ligating reaction is performed by a U-box motif in its carboxy terminus. In association with these chaperones, CHIP plays an essential role in the quality control of misfolded proteins (Tateishi et al, 2004;Younger et al, 2004Younger et al, , 2006Qian et al, 2006).Here, we report that many of the MKKS mutants that are responsible for the MKKS/BBS diseases are degraded in the cell much more rapidly than the wild-type protein and that a CHIP-dependent ubiqutin-proteasome pathway plays a crucial role in this rapid degradation. Although the wildtype MKKS rapidly shuttles between the centrosome and cytosol, rapidly degraded MKKS mutants often fail to localize to the centrosome.…”

“…CHIP interacts with HSC70 and HSP90 through its amino-terminal TPR domain, and the ubiquitin ligating reaction is performed by a U-box motif in its carboxy terminus. In association with these chaperones, CHIP plays an essential role in the quality control of misfolded proteins (Tateishi et al, 2004;Younger et al, 2004Younger et al, , 2006Qian et al, 2006).…”

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.…”

“…[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.…”

“…11 The function of CHIP with its molecular chaperones has been well documented to reduce cellular toxicity associated with several neurodegenerative diseases. 11,12,[14][15][16][17][18] However, the mechanisms underlying how function of CHIP is regulated and, if any, the pathophysiological cascades contributing to CHIP-mediated neurodegeneration are not fully elucidated yet.…”