CHIP: A Co-chaperone for Degradation by the Proteasome - The Networking of Chaperones by Co-chaperones - page 216

Chapter 11
CHIP: A Co-chaperone for Degradation
by the Proteasome

Adrienne L. Edkins

Abstract Protein homeostasis relies on a balance between protein folding and pro-
tein degradation. Molecular chaperones like Hsp70 and Hsp90 fulfil well-defined
roles in protein folding and conformational stability via ATP dependent reaction
cycles. These folding cycles are controlled by associations with a cohort of non-cli-
ent protein co-chaperones, such as Hop, p23 and Aha1. Pro-folding co-chaperones
facilitate the transit of the client protein through the chaperone mediated folding
process. However, chaperones are also involved in ubiquitin-mediated proteasomal
degradation of client proteins. Similar to folding complexes, the ability of chaper-
ones to mediate protein degradation is regulated by co-chaperones, such as the C
terminal Hsp70 binding protein (CHIP). CHIP binds to Hsp70 and Hsp90 chap-
erones through its tetratricopeptide repeat (TPR) domain and functions as an E3
ubiquitin ligase using a modified RING finger domain (U-box). This unique com-
bination of domains effectively allows CHIP to network chaperone complexes to
the ubiquitin-proteasome system. This chapter reviews the current understanding
of CHIP as a co-chaperone that switches Hsp70/Hsp90 chaperone complexes from
protein folding to protein degradation.

Keywords CHIP ﾷ STUB1 ﾷ Ubiquitin ﾷ Proteasome

Introduction to Ubiquitin Modification and Proteasomal
Degradation of Proteins

The ubiquitin proteasome system is a highly conserved mechanism through which
eukaryotic cells facilitate the controlled enzymatic degradation of unwanted pro-
teins (Amm et al. 2014 ; Ciechanover 1998 ). The ubiquitin and proteasome sys-
tems work in concert to regulate protein levels in eukaryotic cells (Roos-Mattjus
and Sistonen 2004 ; Wolf et al. 2004 ; Lecker et al. 2006 ). The proteasome not