Qian SB, McDonough H, Boellmann F, Cyr DM, Patterson C.
CHIP-mediated stress recovery by sequential ubiquitination of substrates and Hsp70.
Nature. 2006 Mar 23;440(7083):551-5.
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Chipping away at HSP70 regulation
This week’s Nature presents an elegant article by Cam Patterson’s group documenting a novel regulatory axis controlling Hsp70 levels. CHIP is a ubiquitin ligase that binds to Hsp70. CHIP is known to mediate induction of Hsp70 in response to stress by inducing activity of the transcription factor HSF-1. The current manuscript describes a second point in the regulatory axis of Hsp70 where CHIP acts. Patterson’s group found that CHIP mediates degradation of Hsp70 during the recovery phase after stress has been quenched. An elegant aspect of this model is that CHIP senses the level of misfolded proteins, and as the level of misfolded proteins decreases, CHIP switches from ubiquitinating these proteins to ubiquitinating Hsp70, which targets it for degradation by the proteasome. Thus, CHIP acts at two points in the regulation of Hsp70. CHIP regulates the transcription of Hsp70 (via HSF-1) and regulates degradation of Hsp70 (via ubiquitination of Hsp70).
The disposition of misfolded proteins is clearly one of the central issues in neurodegenerative research. Hsp70 plays a key role as a chaperone for misfolded proteins, helping either to refold them or to send them for degradation. By regulating levels of Hsp70, CHIP clearly is a primary player in this process. Interest in CHIP is heightened by the discovery that CHIP ubiquitinates tau protein in a process that shifts it to an insoluble protein fraction (1,2). CHIP also binds to parkin, which is linked to familial parkinsonism (1). Patterson’s work provides a valuable framework that greatly enhances our understanding of the ubiquitin proteasomal system.
Petrucelli L, Dickson D, Kehoe K, Taylor J, Snyder H, Grover A, De Lucia M, McGowan E, Lewis J, Prihar G, Kim J, Dillmann WH, Browne SE, Hall A, Voellmy R, Tsuboi Y, Dawson TM, Wolozin B, Hardy J, Hutton M.
CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation.
Hum Mol Genet. 2004 Apr 1;13(7):703-14.
Shimura H, Schwartz D, Gygi SP, Kosik KS.
CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival.
J Biol Chem. 2004 Feb 6;279(6):4869-76.
CHIPs Ahoy: Hsp70 Is Called to Serve and Then Consumed
Almost 30 percent of all cellular proteins are formed without being properly folded. By mutation or through various protein modifications associated with neurodegenerative diseases, additional specific ones become misfolded. To maintain homeostasis in a crowded protein milieu, a quality control system engages molecular chaperones to properly (re)fold proteins at risk for aggregation or facilitate their disposal by the ubiquitin-dependent proteasome (UPS). The "C-terminus Hsc70 interacting protein" (CHIP) is a bi-functional molecular co-chaperone that links molecular chaperones to the UPS (McClellan and Frydman, 2001; McDonough and Patterson, 2003). The CHIP amino terminus has three tetratricopeptide repeat (TPR) domains, responsible for protein-protein interactions with heat shock proteins (HSP)70/90 and other molecular chaperones Hip, Hop, Cyclophilin 40, FKBP, Bag1, etc. (Connell et al., 2001; Kampinga et al., 2003; Dai et al., 2005; Hwang et al., 2005). The CHIP C-terminus contains a U-box or RING finger-like domain endowed with ubiquitin E3 ligase activity toward several substrates (Arvind et al., 2000). Since CHIP also activates heat shock transcription factor-1 (HSF-1), thus controlling Hsp70 induction (Dai et al., 2003), it plays a major role in orchestrating the protein quality control system (Jiang et al., 2001; Demand et al., 2001; Cyr et al., 2002; Hatakeyama et al., 2004; Xu et al., 2002)
In the present paper, several hypotheses about CHIP function were tested, highlighting the regulation of Hsp70 turnover. The authors have shown that CHIP influences Hsp70 levels by another mechanism that is independent of HSF1 transcriptional activation and opposite in effect. After calling up Hsp70 to chaperone misfolded proteins for ubiquitin-dependent and CHIP-mediated proteasomal destruction, CHIP then targets the same Hsp70 to a similar fate. However, it only prepares the unneeded Hsp70 for disposal once the un- or misfolded substrate level is effectively depleted. The "stress recovery" effect is specific to Hsp70, since a slight difference of amino acid sequence with Hsc70 in the C-terminal region (EEVD motif) results in only modest proteasomal degradation of the latter. The authors elegantly show that a sort of non-mutual competition between Hsp70 and substrate exists for CHIP's ubiquitination action. Thus, higher levels of Hsp70 do not inhibit unfolded protein (BSA) turnover. CHIP is sensing only stress protein levels in its decision to terminate Hsp70. So, when CHIP is busy preparing a misfolded protein (luciferase) for degradation, Hsp70 levels are stabilized. When the substrate is either in its normal conformation or levels of its denatured form are eliminated, CHIP then turns on Hsp70 to reestablish basal levels.
Several important implications, predictions, and questions arise from this work. The coordinated rise and rapid fall in Hsp70 levels post-stress suggest that inducibility is essential to optimal chaperone function. What happens then to the biphasic regulation of Hsp70 in neurodegenerative diseases where the misfolded protein chronically accumulates? Could chronic elevations of Hsp70 possibly be deleterious to the cell? Where confounding toxic proteins build up, such as tau and Aβ in AD, could a therapeutic elimination of p-tau (a substrate for CHIP) result in a down-regulation of Hsp70 levels, effectively removing this protective mechanism (as we have shown; Magrane et al., 2004) to neutralize intracellular Aβ? It is also possible that a defect in the Hsp response may exacerbate neurodegenerative disease. For instance, Qian et al. show that in HSF-1-null cells, CHIP expression and activity induces degeneration after heat shock stress. On the other hand, in CHIP-/- cells, where basal Hsp70 levels are higher than WT, the Hsp70 response to heat shock is still present but lessened as expected. Although cell viability is not given, one would predict such cells to also fare worse.
There are other interesting observations from this excellent paper to digest. For instance, the question arises whether the Hsp70 that is stress-recovered is use-dependent modified in some way for recognition by CHIP to be ubiquitinated. This was partly answered when the authors showed that in HSF-1-/- cells (or in CHIP-/- cells treated with cyclohexamide), expression of CHIP in absence of stress or misfolded proteins causes basal Hsp70 degradation. Another prediction is that if CHIP activity could be shut off at the 4-hour point after heat shock, that Hsp70 levels would remain high. However, this result was essentially shown in an experiment using a mutant CHIP construct (H260Q) in which the Ubox/ligase activity is lost but HSF-1 stimulating activity is retained.
In the past 7 years, involvement of CHIP as a molecular sensing switch in neurodegenerative disease has been increasingly recognized. CHIP appears to play a dual role in familial Parkinson disease, where it assists in the dissociation of Hsp70 from a complex with parkin and PAEL-R, facilitating parkin mediated PAEL-R ubiquitination (Imai et al., 2002). CHIP mediates the degradation of α-synuclein by triaging between proteasomal and lysosomal pathways (Shin et al., 2005). CHIP appears to play a role in mitigating tauopathies. It polyubiquitinates 4 repeat-phosphorylated tau, attenuating tau aggregation and enhancing cell survival viewed (Hatakeyama et al., 2004; Petrucelli et al., 2004; Sahara et al., 2005). Its range of substrates may be even greater, as we reported last fall that βAPP is bound to and regulated by CHIP (Kumar et al., Neurosciences Meeting, 2005). There may be something to the idea that dual-function proteins are involved in neurodegenerative disorders where loss of homeostasis and self-perpetuating mechanisms occur.
McClellan AJ, Frydman J.
Molecular chaperones and the art of recognizing a lost cause.
Nat Cell Biol. 2001 Feb;3(2):E51-3.
McDonough H, Patterson C.
CHIP: a link between the chaperone and proteasome systems.
Cell Stress Chaperones. 2003 Winter;8(4):303-8.
Connell P, Ballinger CA, Jiang J, Wu Y, Thompson LJ, Höhfeld J, Patterson C.
The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins.
Nat Cell Biol. 2001 Jan;3(1):93-6.
Kampinga HH, Kanon B, Salomons FA, Kabakov AE, Patterson C.
Overexpression of the cochaperone CHIP enhances Hsp70-dependent folding activity in mammalian cells.
Mol Cell Biol. 2003 Jul;23(14):4948-58.
Dai Q, Zhang C, Wu Y, McDonough H, Whaley RA, Godfrey V, Li HH, Madamanchi N, Xu W, Neckers L, Cyr D, Patterson C.
CHIP activates HSF1 and confers protection against apoptosis and cellular stress.
EMBO J. 2003 Oct 15;22(20):5446-58.
Magrané J, Smith RC, Walsh K, Querfurth HW.
Heat shock protein 70 participates in the neuroprotective response to intracellularly expressed beta-amyloid in neurons.
J Neurosci. 2004 Feb 18;24(7):1700-6.
Imai Y, Soda M, Hatakeyama S, Akagi T, Hashikawa T, Nakayama KI, Takahashi R.
CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity.
Mol Cell. 2002 Jul;10(1):55-67.
Shin Y, Klucken J, Patterson C, Hyman BT, McLean PJ.
The co-chaperone carboxyl terminus of Hsp70-interacting protein (CHIP) mediates alpha-synuclein degradation decisions between proteasomal and lysosomal pathways.
J Biol Chem. 2005 Jun 24;280(25):23727-34.
Hatakeyama S, Matsumoto M, Kamura T, Murayama M, Chui DH, Planel E, Takahashi R, Nakayama KI, Takashima A.
U-box protein carboxyl terminus of Hsc70-interacting protein (CHIP) mediates poly-ubiquitylation preferentially on four-repeat Tau and is involved in neurodegeneration of tauopathy.
J Neurochem. 2004 Oct;91(2):299-307.
Sahara N, Murayama M, Mizoroki T, Urushitani M, Imai Y, Takahashi R, Murata S, Tanaka K, Takashima A.
In vivo evidence of CHIP up-regulation attenuating tau aggregation.
J Neurochem. 2005 Sep;94(5):1254-63.