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...  Read more

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.

References:
1. 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. Epub 2004 Feb 12. Abstract

2. 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. Epub 2003 Nov 10. Abstract

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