CHIP: A Co-chaperone for Degradation by the Proteasome - The Networking of Chaperones by Co-chaperones - page 230

Hsp70 and Hsp90: To Degrade or to Refold?
The chaperone folding and ubiquitin-proteasome degradation pathways work com-
petitively during protein homeostasis (Marques et al. 2006 ). The major question
that remains unanswered is how is it determined whether proteins enter refolding
or degradation pathways? Pro-folding chaperone complexes are largely associat-
ed with the co-chaperone Hop, which facilitates entry of client proteins from the
Hsp70 complex into the Hsp90 complex (Siligardi et al. 2004 ). In contrast, chaper-
one complexes containing CHIP are considered to be pro-degradation complexes.
Hop and CHIP cannot bind simultaneously to the Hsp90 complex, which indicates
that the complexes controlling either protein folding or protein degradation are mu-
tually exclusive and possibly competitive (Kundrat and Regan 2010a ). Therefore,
the simplest mechanism to control the choice of folding or degradation may be via
regulation of the levels of the specific co-chaperone (Marques et al. 2006 ). Indeed,
simply increasing the CHIP concentration by overexpression increased proteasomal
degradation of client proteins, including hormone receptors (Connell et al. 2001 ;
Adachi et al. 2007 ).
Hop and CHIP compete with each other for binding to Hsp70 and Hsp90, which
could determine whether pro-folding or pro-degradation complexes form. There
is evidence that these associations are regulated by post-translational modifica-
tion of the C terminal region of these chaperones. Phosphorylation of sites in the
C-terminus of either Hsp70 or Hsp90 blocked CHIP binding and promoted asso-
ciation of Hop with the chaperones. This observation is particularly important in
the context of cancer, where increased levels of phosphorylated Hsp70 and Hsp90
chaperones have been linked with high cell proliferation rates (Muller et al. 2013 ).
Indeed, many of the kinases that phosphorylated Hsp90, including CK1, CK2 and
GSK3ʲ, are linked to the cell cycle or mitogenic signalling pathways. Hop has also
been shown to be upregulated in numerous cancers, suggesting that increased levels
of this co-chaperone may out-compete CHIP for chaperone binding in these cells
(Willmer et al. 2013 ; Ruckova et al. 2012 ). The net consequence of this would be to
create a cellular environment that promoted protein folding over degradation. The
fact that this is observed in cancer cells may explain the dependency of proteins
on the Hsp70-Hsp90 folding complex and support the high cellular growth rates
observed in most malignancies.
However, protein folding also predominates under physiological conditions.
This is as a result of a greater concentration of chaperone complexes contain-
ing Hop or Hip, than CHIP or BAG-1 (Kundrat and Regan 2010a ). Despite this,
ubiquitination of substrates by CHIP proceeds at a basal level under physiological
conditions. Recent studies by the Regan group suggest that the switch to degrada-
tion of protein clients was largely determined by partitioning of the client protein
between Hsp70 and Hsp90 chaperone complexes (Kundrat and Regan 2010a ).
Hsp70 and Hsp90 can both bind CHIP, but the purported greater affinity of the
CHIP-Hsp70 interaction predicts that this is the dominant complex that mediates
the degradation pathway (Kundrat and Regan 2010a ). Therefore, the interaction