CHIP: A Co-chaperone for Degradation by the Proteasome - The Networking of Chaperones by Co-chaperones - page 222

The Carboxyl Terminus of Hsp70-Interacting Protein
(CHIP)
The carboxyl terminus of Hsp70-interacting protein (CHIP; also known as STIP1
homology and U-box containing protein 1 or STUB1) has dual functions, one
as a co-chaperone of Hsp70 and Hsp90, and the other as an E3 ubiquitin ligase
to regulate proteasomal degradation of chaperone client proteins (McDonough
and Patterson 2003 ; Ballinger et al. 1999 ). In this way, CHIP is a major link
between chaperone mediated folding and protein degradation. CHIP is distin-
guished from the other Hsp90 co-chaperones in that it is primarily involved in
tuning the chaperone complexes towards protein degradation, rather than sup-
porting protein folding (Demand et al. 2001 ). The CHIP gene is conserved in
a range of eukaryotes, being demonstrated or predicted to exist in the genomes
of the human, monkey, mouse, zebrafish, fruit fly, frog, and even the genome
and transcriptome of the recently sequenced Coelacanth ( Latimeria sp. ) (Tastan
Bishop et al. 2014 ). CHIP knockout mice were viable and displayed normal de-
velopment, suggesting that CHIP is not an essential gene (Morishima et al. 2008 ;
Dai et al. 2003 ). However, there was increased peripartum mortality of CHIP null
mice compared to wild type mice. This was attributed to wasting of the thymus,
which is an indicator of reduced ability to cope with stress. The link between
peripartum death of CHIP null mice and stress was subsequently supported by
the fact that CHIP-/- mice were temperature sensitive and that induction of stress
in these animals induced apoptosis in multiple organs after challenge (Dai et al.
2003 ). CHIP overexpression activated the stress response by specifically induc-
ing trimerization and nuclear translocation of HSF-1 and activation of HSE con-
taining stress responsive promoters, like Hsp70 (Dai et al. 2003 ). This suggests
that the role of CHIP is not exclusively linked to protein degradation, but also
involves regulation of the stress response.
Notwithstanding its role in activation of the stress response, CHIP appears to
be a master regulator of protein degradation via chaperones, although it is by no
means the only co-chaperone associated with protein degradation. The Hsp40
isoform, Hsj1 (DNAJB2) (Chapple et al. 2004 ; Westhoff et al. 2005 ; Gao et al.
2011 ) and the nucleotide exchange factor, BAG-1, both have defined roles in
proteasome-mediated protein degradation (Luders et al. 2000 ; Alberti et al. 2002 ;
Alberti et al. 2003 ; Elliott et al. 2007 ). In addition, there are other E3 ubiquitin
ligase proteins (e.g. Ubr1, Cul5, Parkin, Mdm2) that may associate with Hsp90
and/or Hsp70 chaperone complexes to target client proteins for ubiquitination and
degradation (Nillegoda et al. 2010 ; Eisele and Wolf 2008 ; Ehrlich et al. 2009 ).
These proteins are able to induce ubiquitination in the absence of CHIP, although
there is also evidence that inhibition of these E3 ligases can affect protein folding
and degradation even in the presence of CHIP. It is clear that functional redun-
dancy exists between the E3 ligases and is possible that multiple members will
collaborate as a complex to control degradation of specific proteins (Morishima
et al. 2008 ).