CHIP: A Co-chaperone for Degradation by the Proteasome - The Networking of Chaperones by Co-chaperones - page 229

proteins, like HDAC6 and Akt (Cook et al. 2012 ; Dickey et al. 2008 ). Therefore
overexpression of CHIP may represent a therapeutic strategy to prevent neuronal
cell death and ameliorate the symptoms and onset of the disease (Dickey et al.
2007 ; Sahara et al. 2005 ). The role of CHIP in cancer has been relatively less
well studied than neurodegeneration. However, CHIP also controls the proteasomal
degradation of a number of important oncogenic transcription factors or signalling
intermediates, including p53, PTEN, Akt and c-Myc (Paul et al. 2013 ; Kajiro et al.
2009 ; Ahmed et al. 2012 ). These classes of proteins often act as nodes for the acti-
vation of a host of downstream proteins in the cellular reactions that lead to onco-
genesis. Therefore, CHIP may in fact indirectly regulate a larger cohort of cellular
proteins via degradation of central transcription factors or signalling intermediates.
Indeed, analysis of the function of CHIP in breast cancer has demonstrated that the
protein can regulate cellular responses, many of which are considered cancer hall-
marks. Overexpression of CHIP blocked oncogenic signalling pathways, inhibited
cancer associated processes like cell migration and anchorage independent growth,
and induced cell death. Conversely, depletion of CHIP protein levels increased
tumour formation and metastasis in mouse models (Kajiro et al. 2009 ; Choi et al.
2014 ; Sarkar et al. 2014 ).
In addition to classical substrate proteins, CHIP also ubiquitinates the chap-
erones Hsp70 and Hsp90 on multiple solvent exposed, but clustered lysine resi-
dues (6 in Hsp70 and 13 in Hsp90) (Kundrat and Regan 2010b ). The polyu-
biquitination of these chaperones by CHIP occurs via K6, K11, K48, and K63
linkages. The canonical signal for protein degradation is ubiquitination via K48
linkages, and it is known that CHIP can mediate degradation of Hsp70 via this
mechanism (Jiang et al. 2001 ). This reduction in Hsp70 plays a central regula-
tory role to return Hsp70 levels to basal after the induction of the stress response.
However, non-canonical ubiquitin linkages (like K6, K11 and K63) have not
been demonstrated to induce protein degradation, but may mediate other func-
tions. In some experiments, ubiquitination via K63 resulted in recruitment of
Hsp70, Hsp90 and BAG-1 to the proteasome but did not lead to their degradation
(Alberti et al. 2002 ; Jiang et al. 2001 ). This suggested that K63 linkage may be a
proteasome targeting sequence and represent a mechanism by which CHIP uses
the chaperone to deliver its clients to the proteasome (Saeki et al. 2009 ; Chen
and Sun 2009 ).
Ubiquitination of substrates by CHIP does not always lead to proteasomal
degradation via the canonical K48 ubiquitiation. There are some examples in the
literature than demonstrate a role for CHIP in non-canonical ubiquitination of
substrates. One example is the protein, sirtuin, which underwent non-canonical
CHIP-mediated ubiquitination that culminated in its stabilisation and promotion
of DNA repair (Ronnebaum et al. 2013 ). CHIP also mediated T cell activation
by ubiquitination of CARMA1 (Caspase recruitment domain (CARD) containing
membrane-associated guanylate kinase protein 1), a receptor important in anti-
gen receptor linked NF-kappaB signalling. The CHIP mediated ubiquitination of
CARMA1 via K27 was determined to be important for activation of this pathway
(Wang et al. 2013 ).