CHIP: A Co-chaperone for Degradation by the Proteasome - The Networking of Chaperones by Co-chaperones - page 232

contrast, the effect of BAG-1 on steroid receptor function was concentration depen-
dant, being stimulatory at low levels of BAG-1 and inhibitory at higher concentra-
tions of BAG-1 (Knapp et al. 2014 ).
Conclusions
While the molecular mechanisms that are involved in defining the balance between
protein folding and protein degradation are not fully understood, the existence of
CHIP suggests that chaperones actively participate in protein degradation via the
proteasome. This suggests that an as yet undefined mechanism exists to determine
which pathway, folding or degradation, should be followed under certain condi-
tions. Recent studies have demonstrated that CHIP mediated the degradation of a
wide range of cellular proteins, which signifies a central role for this co-chaperone
in protein degradation. Many of these client proteins are important factors in a
range of human diseases; an association that suggests CHIP may be a putative drug
target. The potential applications of CHIP to human disease are likely to be largely
restricted to those that involve either the overexpression or activation of CHIP.
While some experiments demonstrate that CHIP depletion results in degradation of
CHIP substrates, other reports demonstrate that CHIP clients remain unaffected in a
CHIP depleted background. This hints at functional redundancy whereby other E3
ligase factors may compensate for the loss of CHIP. These data may also suggest
that some substrates are more reliant on CHIP for their degradation, whereas others
may be promiscuous with respect to the E3 ligase required for their degradation.
The application of CHIP as a drug target will be limited until we are able to define
the mechanisms which regulate whether chaperones function in protein folding or
protein degradation.
Acknowledgments Financial support for research activities in the laboratory of the author from
the South African National Research Foundation (NRF), Medical Research Council (MRC)
South Africa, Rhodes University and Cancer Association of South Africa (CANSA) is gratefully
acknowledged. The views reflected in this document are those of the author and should in no way
be attributed to the NRF, MRC, Rhodes University or CANSA.
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